bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18729: Prosthetic Valve Positioning - Not a Static Question
Authors: Hall Hurst M
Published: March 2022

A 65-year-old female with a history of bicuspid aortic valve s/p AVR with a Medtronic Hall mechanical valve presented with chest pain. Her recent history was notable for one week of intermittent substernal chest pain present when lying in the left lateral position. Initial ECG, obtained during an episode of chest pain, revealed 2 mm ST segment depression in the anterolateral leads and ST segment elevation in lead aVR. The ECG changes normalized with cessation of her chest pain. Laboratory evaluation showed an INR of 3.5 (on warfarin), and normal cardiac biomarkers. Chest imaging, including CT angiography, was unremarkable. Physical examination demonstrated a normal jugular venous pressure, a mechanical second heart sound, and a II/VI crescendo-decrescendo systolic murmur at the right upper sternal border. Transthoracic echocardiography (TTE) revealed normal biventricular systolic function and a mechanical valve in the aortic position, associated with mild aortic regurgitation.

Valve fluoroscopy revealed an aortic monoleaflet mechanical prosthesis with normal opening and closing angles in the supine position, but with closing restriction when in the left lateral decubitus position (closing angle 46 degrees, associated with recurrent chest pain and ischemic ECG changes). Transesophageal echocardiography (TEE) showed moderate aortic stenosis, mild aortic regurgitation, and multiple linear echodensities on the aortic prosthesis. These echogenicities were felt to represent thrombi, and the patient was treated with 5 doses of tPA and intravenous heparin. Subsequent TEE and valve fluoroscopy revealed improved prosthetic leaflet motion in supine and lateral decubitus positions.

This case describes an unusual presentation of mechanical aortic valve thrombosis. The contiguous association of the mechanical valve with the coronary ostia can contribute to ischemic complications, in this case positionally induced. It also highlights the value of timely valve fluoroscopy and the consideration of patient maneuvers to delineate valve function. Current guidelines support the use of thrombolytic therapy for small, left-sided thrombi, with recent literature suggesting that slowly infused low-dose tPA provides the optimal risk-benefit profile.
Abstract 18750: Systemic Lupus Erythematosus is Associated With Higher In-hospital Mortality Among Patients Hospitalized With Heart Failure: Findings From a United States National Study
Authors: Mazumder Nabila K , Mujib Marjan , Aronow Wilbert S , Gupta Tanush , Paul Neha , Kolte Dhaval , Khera Sahil , Harikrishnan Prakash , Palaniswamy Chandrasekar , Sule Sachin , Ahmed Ali , Frishman William H , Jain Diwakar , Cooper Howard A , Fonarow Gregg C , Panza Julio A
Published: March 2022

Background:
The association between systemic lupus erythematosus (SLE) and heart failure (HF) has been primarily described in case reports and case series. However, the relationship between SLE and clinical outcomes among patients hospitalized for HF has not been systemically evaluated in real-world setting.

Hypothesis:
SLE diagnosis is associated with higher in-hospital mortality among patients hospitalized for acute HF.

Methods:
We used the Nationwide Inpatient Sample (NIS) database to evaluate adult patients who were primarily hospitalized for HF (ICD 9 code 428.xx). Discharge weights were used to enable national estimates. Of 11,992,861 patients hospitalized for HF between 2002-2012, 50,878 (0.4%) had SLE. Logistic regression was used to evaluate the association between SLE and in-hospital mortality among these patients.

Results:
Patients hospitalized for HF had a mean age of 73 (±14) years, 52% were women and 68% were whites. Compared with hospitalized HF patients without SLE, those with SLE were younger (60 years vs. 73 years, P<0.001), more likely to be female and of black race. In-hospital mortality occurred in 2.9% and 3.5% of hospitalized HF patients with and without SLE respectively (unadjusted OR for in-hospital mortality, when HF patients with SLE was compared with HF patients without SLE, 0.81; 95% CI, 0.77-0.85; P <0.001). After adjusting only for age, SLE independently increased risk of in-hospital mortality among HF patients (age adj. OR, 1.22; 95% CI, 1.16-1.28; P <0.001). The association remained statistically significant after adjusting for other patient demographics, risk factors and hospital characteristics (adjusted OR, 1.08; 95% CI, 1.01-1.15; P = 0.019). When compared with HF patients without SLE, those with SLE had a higher mean length of stay (5.68 vs 5.34 days) and higher hospitalization charges ($ 33,330 vs $ 31,098) (all p-values <0.001).

Conclusions:
In this nation-wide study, prevalence of SLE was low among hospitalized HF patients. SLE was independently associated with increased risk of in-hospital mortality, prolonged hospital stay and increased total hospital charge. Further prospective studies are needed to better understand the relationship in this high-risk population.
Abstract 18752: An Ultra-short Cognitive Screening Test to Detect Significant Post-stroke Vascular Cognitive Impairment
Authors: Dong Catherine , Xu Kenny , Chen Christopher
Published: March 2022

Objective:
The National Institute of Neurological Disease and Stroke – Canadian Stroke Network (NINDS-CSN) harmonization battery recommended a 5-minute bedside cognitive screening test drawn from the Montreal Cognitive Assessment (MoCA). However this 5-minute cognitive screening test consisted of (5 word registration, recall, recognition, orientation, animal fluency) was based on expert opinion and not empirical evidence. We therefore aimed to establish an ultra-short cognitive screening test for the detection of post-stroke vascular cognitive impairment (VCI).

Method:
Patients with ischemic stroke/ Transient Ischemic Attack received MoCA within 14 days after stroke and at 3-6 months later. Cognitive outcomes was defined by formal neuropsychological evaluation at month 3-6 and classified as either ‘none-mild VCI (impairment ≤2 domains)’ or ‘moderate-severe VCI (impairment >2 domains)’.

Results:
There were 327 out of 400 patients completed neuropsychological assessments 3-6 months after stroke onset. Of these, 250 (76.5%) had no-mild VCI and 77 (23.5%) had moderate-severe VCI. Most patients were Chinese (70.3%) and males (69.8%) with age of 59.8 ± 11.6 years and education of 7.7 ± 4.3 years. Random forest analysis showed 5 most sensitive items of MoCA for the ultra-short test (5-Min MoCA) at baseline and 3 months to detect significant VCI at 3-6 months. These 5 items were the clock, serial 7s, animal fluency, recall and orientation. Receiver operating characteristic curve analysis showed that MoCA at 3 months had the largest area under curve (AUC) (0.90), followed by 5-Min MoCA at 3-6 months (0.89), baseline MoCA (0.86) and baseline 5-min MoCA (0.83). At 3-6 months, 5-Min MoCA was equivalent to the MoCA and superior to 5-Min MoCA at baseline (p=0.17 and p=0.04, respectively). The cutoff points for 5-Min MoCA at 3-6 months and baseline was the same (cutoff: 12/13 vs 12/13, sensitivity: 0.70 vs 0.74; specificity: 0.87 vs 0.74; classification accuracy: 0.83 vs 0.74, respectively).

Conclusion:
The empirically derived 5-min MoCA differs from the NINDS-CSN 5-min test. The established 5-min MoCA at 3-6 months after stroke is equivalent to the MoCA and superior to the 5-min MoCA at baseline, therefore should be used for routine practice.
Abstract 18781: Elevated Trimethylamine-n-oxide Levels May Contributes to Progression of Cerebral Small Vessel Diseases in Poststroke Patients via Blood Brain Barrier Disruption
Authors: Liu Yuan , Huang Yining
Published: March 2022

Introduction:
High level of serum gut micro-devrived metabolite trimethylamine-N-oxide(TMAO) have recently been association with cardiovascular disease(CVD) and chronic kidney disease(CKD) risk.

Hypothesis:
Here, we aim to test the hypothesis that whether TMAO play a direct contributory role in progression of cerebral small disesase.

Methods:
First, we examined the plasma TMAO level in both subjects with and without cerebral small vessel diseases by liquid chromatography with on-line mass spectrometry (LC/MS) analysis. Further, SD rat were raised with either normal chow diet or normal chow diet supplemented with additional high amounts of TMAO. Animals were killed 14 weeks later and brains were preserved. Paraffin-embedded brain sections were stained using hematoxylin and eosin (HE), anti-claudin5 antibody and anti-ZO1 anti body.

Results:
It is reveals that TMAO level among cerebral small vessel disease is higher than that in normal control subjects. Results also shown that blood brain barrier was disrupted in high TMAO raised group and expression of tight juction proteins decreased. Sample size should be expanded in our following work. What’s more, cell model of blood brain barrier should be established to demonstrated the molecular mechanism of effect of TMAO.

Conclusions:
In conclusion, our study indicates that high serum level of TMAO is association with progression of cerebral small vessel diseases in poststroke patients and raised with diet supplemented with additional high amounts of TMAO lead to blood brain barrier disruption in vivo.
Abstract 18796: Characterization of Endothelial Colony-forming Cells Bioactivity in Young Adults Born Extremely Preterm Versus Term
Authors: Bertagnolli Mariane , Paquette Katryn , Sutherland Megan , Béland Chanel , Lukaszewski Marie-Amélie , Cloutier Anik , Thébaud Bernard , Luu Thuy Mai , Nuyt Anne Monique
Published: March 2022

Introduction:
Among subtypes of endothelial progenitor cells, endothelial colony-forming cells (ECFC) display high proliferative and angiogenic capacity in vitro and are considered biomarkers of angiogenic/regenerative capacity. Cord blood ECFC from preterm born (PT) infants have impaired bioactivity, especially in those who develop prematurity-related complications such as bronchopulmonary dysplasia. Whether ECFC dysfunction persists in PT beyond the neonatal period is not known.

Objective:
Our aim was to assess ECFC bioactivity (in vitro growth, angiogenic capacity) in extremely PT vs. term (T) born young adults.

Methods:
ECFC were obtained from peripheral blood from 19 young adults (21-28 years old) born extremely PT (<29 weeks gestation) and 19 T (≥37 weeks, paired by gender, age and socioeconomic status). Mononuclear cells (PBMC) were separated by density gradient and plated (5x10(6) cells/flask) to allow ECFC colony formation. ECFC were cultured to assess cell phenotype (CD45-/CD34+/CD31+/KDR+), in vitro proliferation rate by modified thymidine analogue EdU incorporation, and tubular formation in Matrigel.

Results:
ECFC colonies were obtained from 9 PT (48%) and 12 T (63%). The frequency distribution of the number of days to first colony formation was significantly different in PT vs. T, with higher frequency of late (> 15 days) and absence of any colony formation in PT (p=0.033). In PT, days to form 1st ECFC colony inversely correlated with ECFC proliferation rate (r=-0.85, p<0.001), and angiogenic capacity shown as number of tubes (r=-0.72, p=0.037) and branches (r=-0.68, p=0.043) formed in Matrigel, whereas in T these correlations were not significant with similar ECFC function at any time of colony formation. In PT, tubular formation negatively correlated with neonatal length of hospital stay (r=-0.72, p=0.03), a proxy of prematurity-related complications.

Conclusions:
Time to first ECFC colony formation, proliferation rate and in vitro tubular formation are significantly altered in PT vs. T young adults. Overall data suggests that extremely PT born young adults display impaired ECFC bioactivity, which may contribute to the development of cardiovascular diseases associated with impaired angiogenesis in this population.
Abstract 18805: Association of State Certificate of Need Regulations With the Appropriateness of PCI Procedures
Authors: Chui Philip W , Parzynski Craig S , Ross Joseph S , Ho Vivian , Spertus John A , Gurm Hitinder S , Curtis Jeptha P
Published: March 2022

Introduction:
Certificate of Need (CON) regulations are intended to limit healthcare infrastructure to control healthcare costs, prevent overuse, and improve quality of care. However, there is limited information about the impact of CON regulations on the use of invasive cardiac procedures. To address this gap, we examined the association of state CON regulations with the appropriateness of percutaneous coronary interventions (PCI).

Methods:
We used data from the ACC’s CathPCI Registry to analyze 1,143,402 PCIs performed at 1,297 hospitals between January 2010 and December 2011. We applied the 2012 Appropriate Use Criteria (AUC) to determine whether the procedure was considered appropriate, uncertain, or inappropriate, and we used chi-square analyses to assess whether the proportions of PCIs AUC categories differed depending on whether the procedure had been performed in a state with or without CON regulations. Analyses were repeated stratified by whether or not the procedure was performed in the setting of an acute coronary syndrome (ACS).

Results:
The characteristics and outcomes of patients undergoing PCI were similar in states with and without CON. The proportion of PCIs considered appropriate in non-CON states was slightly lower compared with CON states (85.5% versus 86.2%), and a higher proportion of procedures were considered inappropriate (4.6% versus 4.2%) [Table]. Absolute differences were larger among non-ACS PCI patients and were not statistically significant among ACS PCI patients.

Conclusions:
States with CON had a lower proportion of inappropriate PCIs as compared with states without CON. However, the absolute differences were small, suggesting that CON regulations alone may have a limited impact on preventing potential overuse of PCI procedures.
Abstract 18811: Improving the Practicality of Echocardiographic Screening for Rheumatic Heart Disease: Performance of Non-expert Users Following Completion of a Standardized Computer-based Training Curriculum
Authors: Beaton Andrea , Nascimento Bruno R , Diamantino Adriana C , Pereira Gabriel T , Lopes Eduardo L , Miri Cassio O , Bruno Kaciane K , Chequer Graziela , Ferreira Camila G , Lafeta Luciana C , Richards Hedda , Perlman Lindsay , Webb Catherine , Ribeiro Antonio L , Sable Craig , Nunes Maria do Carmo P
Published: March 2022

Background:
Echocardiography (echo) is the most sensitive tool for rheumatic heart disease (RHD) detection. However, widespread screening programs are non-existent due to lack of financial and expert human resources in endemic areas. Task-shifting to non-experts to perform RHD screening is promising; however, investigations into workforce composition and replicable training schemes are needed.

Objective:
Test non-experts’ ability to conduct RHD screening following a brief, standardized, computer-based training course.

Methods:
Six non-experts with a variety of backgrounds (nurses, health technicians, medical students) and echo experience (6 wks-1 yr) completed a 3-module computer-based curriculum focusing on simplified criteria for RHD screening (mitral regurgitation (MR) ≥1.5cm and/or any aortic regurgitation). Following training, two teams of 3 non-experts were placed in school screening environments. Gold-standard diagnoses of RHD (2012, World Heart Federation criteria) were made by cardiologists using standard portable echo equipment. Children diagnosed with RHD and 25% of the general screening population was blindly evaluated by each non-expert using the simplified criteria with handheld echo.

Results:
Screening was performed in 1,381 children, with 397 (47 borderline RHD, 6 definite RHD, 336 normal & 8 other) referred for handheld echo (209 Team 1 & 188 Team 2). Age ranged from 5-18 years (mean 13.6); 59% were female. Overall sensitivity of the simplified approach was 90.8% (95% CI 85.4-94.6%; range 75-100%), with an overall specificity of 82.4% (95% CI 79.9-84.7%; range 75-89%). The most common reasons for false-negative screens (n=16) were missed MR (44%) and MR ≤1.5cm (29%), and for false-positive screens (n=179) included identification of erroneous color jets (25%), incorrect MR measurement (24%), and appropriate application of simplified guidelines (MR between 1.5 and 2.0 cm, 39.4%).

Conclusions:
A short, computer-based curriculum can be successfully used to train a heterogeneous group of non-experts to preform large-scale RHD screening. This simplified approach addresses prohibitive financial and workforce barriers to widespread RHD screening and holds the potential to significantly reduce the global burden of RHD.
Abstract 18834: IF1 And ApoA-I Serum Concentrations, but Not HDL-cholesterol, Predict Mortality in Coronary Artery Disease Patients: The Genes Study
Authors: Genoux Annelise , Ruidavets Jean-Bernard , Ferrières Jean , Bongard Vanina , Vervueren Paul-Louis , Combes Guillaume , Taraszkiewicz Dorota , Elbaz Meyer , Perret Bertrand , Martinez Laurent O
Published: March 2022

Introduction:
High-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL for assessing cardiovascular risk. Serum inhibitor factor 1 (IF1), an endogenous inhibitor of the ecto-F1-ATPase apoA-I receptor, has been identified as an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD).

Objective:
To determine the relationship between serum IF1 concentration and mortality in stable CAD patients in comparison with HDL-C and apoA-I

Methods:
Serum IF1 was measured in 577 coronary male patients (enrollment age 45-74 years; enrollment period, 2001-2004) from the GENES (Genetique et ENvironement en Europe du Sud) study. Vital status was assessed yearly through December 31, 2013.

Results:
During a median follow up of 11 years, mortality rate was 29.5%. Cardiovascular mortality accounted for the majority (62.5%) of deaths. Serum IF1 (median value: 0.42 mg/mL) was positively correlated with HDL-C and apoA-I, and negatively with triglycerides and the severity of CAD (Gensini, Duke-Jeopardy scores). Mortality was lower the higher the quartile score for IF1 and apoA-I, but not for HDL-C. Inverse associations of IF1 and apoA-I with mortality remained significant, even after multivariate adjustments for classical cardiovascular risk factors - age, smoking, diabetes, dyslipidemia, waist circumference, physical activity and CRP. Furthermore, associations of the highest IF1 quartile with mortality reduction remained significant after further adjustment for clinical parameters proven to be predictive of complications in CAD patients, such as ankle-brachial index, heart rate and CAD duration. Interestingly, when levels of both IF1 and apoA-I were high, mortality was much lower than when only one of these was high.

Conclusions:
IF1 is a new biological marker strongly predictive of mortality in CAD patients. Among patients with normal or elevated apoA-I levels, IF1 measurement may help to identify those who are at low risk of complications and those who are not. IF1 measurement could be use in a panel of other emerging biomarkers that have been proven to be better than HDL-C level, for the better assessment of cardiovascular risk or in the setting of pharmacotherapy.
Abstract 18871: Coagulation Factor Xa Promotes Endothelial Cell Senescence Via P53 Up-regulation
Authors: Sanada Fumihiro , Taniyama Yoshiaki , Muratsu Jyun , Otsu Rei , Rakugi Hiromi , Morishita Ryuichi
Published: March 2022

Factor Xa (FXa) occupies a central place in coagulation cascade as a convergence point between intrinsic and extrinsic pathways. Apart from this activity, the non-hemostatic function of FXa through protease activated receptors (PARs) triggers an intracellular activation that can initiate signaling cascades regulating migration and survival of cells. However, the direct effect of FXa on angiogenesis in endothelial cells (ECs) and endothelial progenitor cells (EPCs) is largely unknown. Here, we demonstrated that FXa treatment on both ECs and EPCs significantly increases the expression of p53 protein through PAR2 (p<0.05). Activation of p53 proteins resulted in impairment of migration and tube formation of these cells. Moreover, chronic FXa stimulation on ECs and EPCs induced cell senescence assessed by Senescence-associated beta-galactosidase (SA-β-gal) staining (p<0.05). These unfavorable effect of FXa on ECs and EPCs were diminished by co-treatment with FXa inhibitor, rivaroxaban. To test whether these in vitro observation has an in vivo counterparts, chronically treated EPCs with FXa were intravenously injected immediately after femoral artery ligation in mouse ischemic hind limb model. Laser doppler image (LDI) analysis showed that EPCs enhanced the recovery of ischemic limb perfusion and this beneficial effect of EPC was significantly blunted by FXa. Additionally, the increase in capillary density by EPCs injection was inhibited by the treatment with FXa. However, treatment with rivaroxaban significantly increased ischemic limb perfusion and capillary density compared to FXa treatment group (p<0.05). In summary, these observation indicates anti-angiogenic property of FXa via p53 upregulation. FXa inhibitor, rivaroxaban, might work as anti-senescence and maintain angiogenic ability of ECs and EPCs.
Abstract 18885: CTRP1, an Adipokine Causing Endothelial Dysfunction Through Upregulation of Arginase 1, is Associated With the Severity of Coronary Artery Disease in Patients and Promotes Atherogenesis in Mice
Authors: Wang Xiao Qun , Lu Lin , Zhang Rui Yan , Liu Zhu Hui , Shen Ying , Wang Ling Jie , Yan Xiao Xiang , De Caterina Raffaele , Shen Wei Feng
Published: March 2022

Background:
C1q/TNF-related protein (CTRP) 1 was initially identified as a paralog of adiponectin based on the similarity in C1q domain of these two proteins. However, vascular functions of CTRP1 remain largely undetermined. Here, we sought to investigate whether CTRP1 influences the pathogenesis of atherosclerosis.

Methods and Results:
We analyzed CTRP1 levels in sera of coronary artery disease (CAD) patients (n=451) and non-CAD controls (n=686), in coronary endarterectomy specimens (n=26) and non-atherosclerotic internal mammary arteries (n=32), and in peripheral blood mononuclear cells (PBMCs) from severe CAD patients (n=58) and non-CAD controls (n=25). CTRP1 levels were higher in sera, endarterectomy specimens and PBMCs from CAD patients compared with controls, and were related to CAD severity. Immunohistochemistry of human femoral arteries exhibited VE-cadherin loci-associated increased CTRP1 expression in atherosclerotic plaques. In cultured endothelial cells, CTRP1 stimulation resulted in reduced nitric oxide (NO) bioavailability and promotion of inflammatory reactions (increased production of inflammatory cytokines and induction of adhesion molecules). Intravital microscopy exhibited impaired endothelium-dependent arteriole dilation and enhanced leukocyte-endothelium interactions after injection of recombinant CTRP1, whereas improved arteriole dilation and decreased leukocyte-endothelium interactions were observed in CTRP1 knockout mice. Furthermore, we found that arginase 1 was significantly increased by CTRP1 in a dose-dependent fashion, thereby leading to eNOS-uncoupling and reactive oxygen species generation. Inhibition of arginase activity by synthetic chemicals markedly improved CTRP1-dependent endothelial dysfunction. Finally, intraperitoneal injection of recombinant CTRP1 promoted atherogenesis in apoE-/- mice. In contrast, proatherogenic effects were significantly attenuated in CTRP1-/-/apoE-/- double knockout mice.

Conclusions:
Our findings have demonstrated that CTRP1 is a pro-atherogenic adipokine, likely by modulating arginase 1 expression and enzyme activity. CTPP1 may represent a crucial therapeutic target in atherosclerosis.
Abstract 18888: 2-Methoxyestrone Retards the Progression of Angioproliferative Pulmonary Hypertension in Rats - Role of 17beta-Hydroxysteroid Dehydrogenase Pathway
Authors: Hu Jian , Rafikova Olga , Schneider Frank , Jackson Edwin K , Tofovic Stevan
Published: March 2022

Background:
2-Methoxyestradiol (2ME2; major non-estrogenic metabolite of estradiol) attenuates monocrotaline (MCT)- and SU5416+hypoxia (SU/Hx)-induced pulmonary arterial hypertension (PH). 2ME2 is dehydrogenated by type-2 17β-hydroxysteroid dehydrogenase (17-HSD2) to 2-methoxyestrone (2ME1), a metabolite with no biological activity. However, in vivo 2ME1 may be converted back to 2ME2 by type-1 17β-HSD (17-HSD1). Our recent study indicates that 2ME-2 and all-trans retinoic acid (atRA; a 17HSD1 inducer) have synergistic therapeutic effects in MCT-induced PH.<

Methods:
To study the role of 17β-HSD metabolic pathway on development of PH, first we examined the effects of 2-ME1 on proliferation of human pulmonary artery smooth muscle cells (hPASMC), lung fibroblasts (hLF) and hela cells, in the presence or absence of atRA. Next, in male rats, we studied the effects of 2ME1 on progression of MCT-induced PH (Day14-28 post MCT). Finally, we investigated the effects of 2ME1 on SU/Hx-induced PH. Ten days into hypoxia, intact (F) and ovariectomized (OVX) female rats were implanted minipumps delivering vehicle (PEG-400 0.5μl/h; F-SU and OVX-SU groups) or 2-ME1 (20μg/kg/h; F-2ME1 and OVX-2ME1 groups)

Results:
In hPASMC, hLF and hela cells 2ME1 had no/modest antimitogenic effect at a high pharmacological concentration, whereas in the presence of atRA, 2ME1 exhibited strong and concentration-dependent inhibition of cells growth. In male rats, 2ME1 retarded the progression of MCT-PH, and attenuated right ventricle (RV) and pulmonary vascular remodeling. In female rats SU/Hx induced severe angioproliferative PAH (RVPSP: F=23+2 vs F-SU = 116+10mmHg) and 2ME1 reduced PAH. Ovariectomy attenuated PAH (RVPSP: F-SU= 116+10 vs F-2ME1=96+10mmHg and in OVX-SU rats 2ME1 significantly retarded the progression of disease (RVPSP: OVX-SU= 99+9 mmHg vs. OVX-2ME1= 71+4) and markedly reduces RV remodeling (RV/LV+S: OVX-SU=0.715+0.021 vs. OVX-2ME1=0.555+0.026; p<0.001)

Conclusions:
This study provides the first evidence that in vivo 2ME1 is biologically active and has therapeutic effects in angioproliferative PAH. Presented data suggest that 17β-HSD pathway of estradiol metabolism may play significant role in development and/or progression of PH.
Abstract 18901: Endothelium Based Feeder Improves Capacity of Human Embryonic Stem Cells Derived Cardiomyocytes
Authors: Pasquier Jennifer , Hoarau-Véchot Jessica , Riout Damien , Gupta Renuka , Abu-Kaoud Nadine , Abi Khalil Charbel , Rafii Shahin , Rafii Arash
Published: March 2022

Introduction:
The regenerative ability of the heart is very low, making patients with myocardial damage potential candidates for cell-based regenerative therapy. Pluripotent human embryonic stem cells (hESC) are a promising source of cardiomyocytes (CMs). While the quantity of CMs obtained is no longer a limitation in current differentiation protocols, their functionality remains to be improved. Indeed contracting areas in cell cultures are still heterogeneous and non-consistent

Hypothesis:
Endothelial cells (ECs) and CMs are derived from a common precursor. Moreover, endothelial secreted and contact dependent factors play a role at different phases of cardiac development and repair. We hypothesized that creating a mixture of cell types that more closely resembles heart tissue - i.e. containing both ECs and CMs - will lead to improved maturation and functionality

Methods:
We co-cultured NKX2-5-GFP reporter hESC line and an autonomous Akt-activated ECs and induced differentiation of NKX2-5GFP hESC into CMs We assessed functionality by evaluating beating and coordination between different CMs clusters.

Results:
Around 94% ± 6 of the NKX2-5GFP+ cells were beating when hESCs embryonic body (EBs) were plated on E4+ECs comparing to 34% ± 12.9 for controls. The spatial organization of beating areas in co-cultures was different. In 7 different experiments clustered in two populations, the average BPM of CMs in co-culture was faster and closer to a physiologic heart rate compare to controls (49.6 ± 13.77; n=13 vs 24.76 ±9.36; n=8 for controls; p<0.05). Our protocol increased and accelerated the differentiation of CMs. More importantly CMs formed under these conditions displayed a higher rate of contractility with synchronized beating relying on an endothelial network.

Conclusions:
We have been able to build a culture platform in vitro capturing partially complexity of cardiac tissue. Such strategy resulted in the obtaining of more synchronized interconnected CMs nodes displaying faster beating. Our data showed that co-culture of differentiating hESCs with ECs increased functionality of the CMs, suggesting that an endothelial based feeder could promote the in vitro functionalization of clinically relevant cell type.
Abstract 18911: Relaxin-2 Levels and Early Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study
Authors: Damp Julie , Givertz Michael , Semigran Marc , Felker Michael , Boehmer John , Skopicki Hal , Bozkurt Biykem , Ewald Gregory , Alharethi Rami , Hanley-Yanez Karen , Halder Indrani , McNamara Dennis M ,   for the IPAC Investigators
Published: March 2022

Introduction:
Relaxin-2 is a polypeptide hormone which is elevated in peripartum women. Recombinant relaxin-2 is under investigation as a therapy for acute heart failure. Whether endogenous relaxin influences myocardial function in peripartum cardiomyopathy (PPCM) has not been previously investigated. We investigated the impact of relaxin-2 on recovery in PPCM in the multicenter Investigations of Pregnacy Associated Cardiomyopathy (IPAC) study.

Methods:
98 women with PPCM were enrolled and serum obtained at entry. LVEF was assessed by echocardiography at entry, 2 months, 6 months and 12 months. Relaxin-2 levels were measured by ELISA. Myocardial recovery was evaluated by tertiles of relaxin at entry for the entire cohort (n=98). Given that relaxin-2 levels were most elevated early, we then reevaluated the impact of relaxin specifically in subjects enrolled in the first quartile based on days postpartum to entry.

Results:
Overall the cohort was 30% black 65% white and 5% other. Mean age was 30
+
6 years, LVEF 0.35
+
0.10 and time to entry 31
+
25 days post-partum. The mean relaxin level was 29
+
110 pg/ml and dropped rapidly postpartum (correlation r= -0.42, p<0.001, mean relaxin2 for post postpartum quartiles=97
+
203 (0 to 11 days), 10
+
31 (12 to 24), 4
+
2(25 to 51), 5
+
7 (51 to 95),p=0.004. For relaxin tertiles analysis for the overall cohort, subjects with the highest levels at entry had the highest mean LVEF at 2 months postpartum, (LVEF high/intermediate/low relaxin= 0.47
+
0.10/0.44
+
0.10/0.39
+
0.10,p=0.01). When reevaluated only in women presenting in the first quartile( n=25, days postpartum 6.5 +3.2 , range 0 -11 days), LVEF at 2 months was again higher in those with the highest relaxin levels (relaxin tertiles high/intermediate/low =0.53
+
0.10/ 0.45
+
0.09/0.38
+
0.11, p=0.02) with a trend at 6 months (p=0.09) and 12 months(12 month LVEF tertiles=0.55
+
0.08/ 0.53
+
0.09/0.47
+
0.14, p=0.19).

Conclusions:
In women with PPCM, higher relaxin-2 levels were associated with early myocardial recovery and higher LVEF at 2 months.Endogenous relaxin appears play a cardio protective role in PPCM. The role of treatment with recombinant relaxin to facilitate myocardial recovery in PPCM remains to be determined.
Abstract 18919: Awareness of Hands-only CPR in an Urban Minority Population
Authors: Balakrishnan Revathi , Axsom Kelly , Roswell Robert , Phillips Lawrence , Katz Stuart
Published: March 2022

Introduction:
Hands-only CPR has been associated with improved survival rates for out of hospital cardiac arrest. There is wide geographic variation in bystander CPR rates and increased barriers to CPR knowledge in minority populations. Our aim was to assess the awareness and willingness to perform hands-only CPR in an ethnically diverse population.

Methods:
English-speaking patients in primary care and cardiac subspecialty clinics were approached to answer a 33 question survey. Demographic information was collected, and awareness of CPR and hands-only CPR was assessed. A brief instructional video of hands-only CPR was administered and willingness to perform hands-only CPR was assessed after.

Results:
Of 255 approached, 127 completed the survey. 53.4% were Hispanic or Black, and 81% spoke English at home. Median age was 49 years old, and majority were male (63%). 48% had a cardiac history or had a friend or family member with heart disease. 61% had no prior CPR training. The most common reasons identified for not doing CPR were fear of doing it incorrectly (33%) and no training (28%). 52% were unaware of hands-only CPR and 52% were unsure or unwilling to do CPR on a stranger. Willingness to perform CPR on a stranger was associated with higher educational level and prior training. After viewing the hands-only CPR instructional video,93% of those who were initially unsure or unwilling to do CPR were significantly more likely to do hands-only CPR (p<0.001).

Conclusions:
In this predominantly minority population, we found reduced awareness of hands-only CPR and demonstrated that an educational video can increase willingness to perform hands-only CPR. This educational tool can be used to target areas and populations where bystander CPR rates are low.
Abstract 18936: Fluid Shear Stress Regulates Expression of Coxsackievirus-adenovirus Receptor Through Mechanosensory Complex in Endothelial Cells
Authors: Chung Jihwa , Lee Ga-Young , Kim Kyoung Hwa , Lee Yoon Pyo , Lee Seok Cheol , An Shung Hyun , Kwon Kihwan
Published: March 2022

Backgrounds:
Vascular endothelial cells, which form the innermost layer of blood vessels, are exposed to fluid shear stress that modulates endothelial function and vascular pathophysiology. The coxsackie- and adenovirus receptor (CAR) is a transmembrane protein belonging to the immunoglobulin superfamily. However, the function of CAR as a virus receptor has been extensively studied, while its physiological role and expression pattern in endothelial cells under fluid shear stress have remained less clear.

Methods and Results:
We demonstrated that mechanisms involved in CAR expression and underlying molecular mechanism by comparing the laminar and oscillatory fluid shear stresses in endothelial cells. Confluent HUVECs were exposed to a unidirectional steady flow (shear stress of 25 dyne/cm2) for laminar shear stress (LSS), and a bidirectional disturbed flow (shear stress of ± 5 dyne/cm2) for oscillatory shear stress (OSS), under various time periods. Additionally, we used a model of atherosclerosis induced by disturbed flow in mice by partial carotid artery ligation. Western blot and RT-PCR analyses in HUVECs showed that OSS has upregulated CAR expression in both protein and mRNA levels; on the other hand, LSS has downregulated them. In enface staining of mice with partial carotid artery ligation, ligated left carotid artery (LCA) with OSS showed significantly increased CAR expression compared to expression from normal right carotid artery (RCA). In knockdown of CAR in HUVECs with siRNA encoding CAR, suppression in phosphorylation of Akt and eNOS by OSS was improved, whereas LSS-induced phosphorylation of Akt and eNOS was much activated. Moreover, transfection of HUVECs with siRNA encoding VEGFR2, PECAM-1 and VE-cadherin blocked OSS-induced CAR expression.

Conclusions:
Our results indicate that fluid shear stress can regulate CAR expression in endothelial cells and its regulation is mediated through the mechanosensory complex. Furthermore, it suggests that inhibition of CAR expression may lead to protective effects in endothelial cells via improving stimulation in signaling of mechanosensor under fluid shear stress. (Acknowledgements: NRF-2011-0019695)
Abstract 19005: Identifying the Focal Points of Cardiac Research From Publication Records
Authors: Lam Maggie P , Venkatraman Vidya , Dincer Tevfik U , Lau Edward , Van Eyk Jennifer E , Ping Peipei
Published: March 2022

Introduction:
The human heart expresses ~10,000 genes, but only a subset is most relevant to cardiac disease and medicine. To maximize the impact of new technological developments to cardiac research, it is imperative that valuable resources be allocated such that genes that are most relevant to the cardiac community are prioritized, e.g., to ensure high-quality research reagents on these genes are available and to promote biocuration efforts to annotate their functions.

Hypothesis:
A relatively small number of genes concern the majority of cardiac research efforts, and can be identified from the analysis of publicly available literature records.

Method:
We developed a novel data science method to analyze over one million peer-reviewed cardiac-related publications and the cardiac genes referenced to these articles. We then derived a metric to measure gene importance to cardiac research based on the normalized semantic distance between the gene and articles on various cardiac diseases to which it is referenced. The cardiac genes with the least semantic distance to cardiac publications were retrieved.

Results:
We identified 50 of the most highly investigated genes in the heart, accounting for ~15% of all cardiac research, and constructed gene networks from their publication records and functional annotations. The analysis also allowed us to visualize several major clusters of cardiac research focuses, surrounding the contractile machinery, ion channels, BNP signaling, and PKA signaling. In addition, we identified ~50 proximal genes which are functionally related to critical cardiac processes but currently under-studied, and which we predict will become important research targets in the near future.

Conclusion:
We demonstrate here a big data-driven approach to catalogue and predict the focus and trend of cardiac research.
Abstract 19017: Sex Differences in Severe Pulmonary Arterial Hypertension Produced by SU5416 in a Colony of “Hyper-responsive” Sprague Dawley Rats
Authors: Chaudhary Ketul R , Deng Yupu , Tyson Kurt , Yang Anli , Stewart Duncan J
Published: March 2022

Introduction:
Our lab has identified a sub-strain of Sprague Dawley (SD) rats from Charles River Labs, obtained from a specific colony housed at a Canadian facility (Sherbrooke, Quebec), which develop severe progressive PAH in response to single injection of SU5416 (SU), a VEGFR2 antagonist, even in absence of chronic hypoxia (CH). This trait appears to due to the presence of unique genetic modifiers found only in this colony. Interestingly, there was a strong sex difference with >70% of males and only <30% of females showing the SU hyper-responsive (HR) phenotype. The purpose of the project was to explore the mechanisms contributing to sex related differences in response to SU alone in a hyper-responsive sub-strain of SD rats.

Hypothesis:
Sex dependent differences in the HR phenotype are due to the protective effects of female sex hormones, reducing the susceptibility to PAH in response to VEGFR2 inhibition.

Methods and Results:
Male and female rats were injected with SU (20mg/kg, sc) or vehicle. Right ventricular systolic pressure (RVSP) was measured at four and seven weeks after SU injection. In male SD rats, 72% (13 of 18) of rats exhibited an HR phenotype in response to SU with mean RVSP of 97±18 mmHg in absence of CH; whereas only 27% (7 of 26) of the female rats were responsive to SU alone. We studied the SU responsiveness in the oophorectomized female rats to investigate the role of female sex hormones in the sex-specific HR phenotype. Interestingly, the proportion of HR animals increased drastically in oophorectomized female rats to 71% (10 of 14), compared to non-operated female rats (33%, 4 of 12). Moreover, estradiol replacement completely abrogated the HR phenotype in both male rats and oophorectomized female rats.

Conclusion:
These data support a role of female sex hormones in modulating the development of severe PAH in response to SU alone in a unique colony of SD rats that exhibit increased sensitivity to VEGFR2 blockade. The HR SD rat colony model exhibits exquisite sensitivity to estrogen and thus provides a unique opportunity to further define the complex interactions between hormonal and genetic modifiers in the development of PAH.
Abstract 19037: Impact of the GNB3 C825T Polymorphism on Heart Failure Survival
Authors: McNamara Dennis M , Hanley-Yanez Karen , Halder Indrani , Sheppard Richard
Published: March 2022

Introduction:
Genetic background can influence heart failure survival and the impact of therapeutics. A polymorphism of a G protein beta subunit, GNB3 C825T, has been investigated extensively for its impact on the genomic risk of hypertension. The T allele is associated with low renin hypertension and increased alpha adrenergic tone. The T allele is more prevalant in African Americans and in the AHeFT trial was associated with a greater impact of therapy with a fixed dose combination of hydralazine and isosorbide dinitrates. We investigated the impact of GNB3 C825T on transplant free survival in systolic heart failure in GRACE (Genetic Risk Assessment of Cardiac Events), a singe center study based in an outpatient heart failure clinic.

Methods:
944 subjects with systolic heart failure were enrolled from the Heart Failure Clinic at the University of Pittsburgh and followed for up to 5 years to an endpoint of death or cardiac transplantation. Demographic information was recorded at the time of enrollment and medical therapy reassessed annually. Blood was obtained at entry for DNA banking, and the GNB3 C825T genotype was determined. Transplant free survival was compared by Kaplan Meier log rank assessment.

Results:
The cohort was 28% female, 13% black, 48% ischemic, mean age 56
+
9, mean LVEF 0.25
+
0.09, and was NYHA class % 1/2/3/4=4%/52%/40%/4%. In terms of the GNB3 genotype the %TT/TC/CC were 16.5%/41.8%/41.7% and the frequency of the T allele differed significantly by race and was more common in Blacks (p<0.001) . During follow up there were 236 (25%) death, and 126 transplants (13%). The T allele was associated with poor transplant free survival (Figure: p=0.025) driven primarily by poorer absolute survival (p=0.017).

Conclusions:
The GNB3 825T allele was associated with poorer survival in a cohort with chronic heart failure. Its role in racial differences in heart failure outcomes warrants futher investigation.
Abstract 19090: Identification and Classification of Descending Aorta Re-entry Sites in Type I Aortic Dissection
Authors: Tsagakis Konstantinos , Dohle Daniel S , Jánosi Rolf A , Schlosser Thomas , Benedik Jaroslav , Wendt Daniel , Thielmann Matthias , Erbel Raimund , Jakob Heinz
Published: March 2022

Introduction:
False lumen patency along the downstream aorta after proximal aortic surgery for acute type I aortic dissection (AD) is associated with poor prognosis. We visualized and evaluated intraoperatively the position and morphology of distal re-entry sites in type I/III AD patients for treatment definition.

Methods:
From 01.2008 - 05.2015 212 patients underwent surgery for AD via median sternotomy. In 124, acute (n=87) or chronic (n=37) type I/ III AD, a flexible videoscope, called angioscope, was used during the open arch repair for visualization of the descending aorta. The procedure was performed under isolated selective cerebral perfusion and hypothermic circulatory arrest distally. The position of the distal intimal lesions was defined according to the distance to left subclavian artery (LSA) origin. The lesions were classified as disrupted intercostal arteries, vertical- and oval- shaped lesions and circumferential obliteration of the intimal wall. The information was used for ad hoc extension of the aortic treatment.

Results:
In 102/124 a total of 188 intimal lesions were identified, mean±SD 1.47±1.22/patient. In 22 no re-entry was found. Within 5cm, 6-10cm, 11-15cm and 16-20cm distal from the LSA reentries were found in 73%, 31%, 14% and 11% of the patients, respectively. Disrupted intercostal arteries were found in 42%, vertical in 36% and oval in 19%. A circumferential obliteration of the intimal wall was identified in 3% and only in chronic AD. Re-entries were excluded using the frozen elephant trunk (FET) technique in 94/124 obtaining a false lumen thrombosis in 94%. The angioscopy rescued the FET procedure from severe complication in 7 and guided antegradely a FET extension by a second graft in 2 patients.

Conclusions:
The angioscopy of the downstream aorta enables the identification and classification of re-entries in patients underwent open arch surgery for AD. Visualization of the descending aorta pathology warrants the safety of endovascular treatment via the open arch.
Abstract 19159: Performance of T1 Mapping Cardiac Magnetic Resonance Imaging as Compared to Biventricular Endomyocardial Biopsy in Patients With Suspected Myocarditis
Authors: Lurz Philipp , Luecke Christian , Foehrenbach Felix , Frank Clara , Eitel Ingo , Sandri Marcus , Boudriot Enno , de Waha Suzanne , Klingel Karin , Kandolf Reinhard , Schuler Gerhard , Thiele Holger , Gutberlet Matthias
Published: March 2022

Background:
The diagnostic performance of cardiac magnetic resonance (CMR) imaging in suspected myocarditis is still limited. Recently, CMR T1 mapping has been suggested to yield excellent diagnostic accuracies in patients with suspected myocarditis as compared to healthy controls. However, the true diagnostic performance of T1 mapping when compared to endomyocardial biopsy (EMB) in patients with a variety of pathologies is till unknown and was therefore assessed in this study.

Methods and Results:
Within the final analyses, 129 consecutive patients with suspected acute or chronic myocarditis were included. Patients had to fulfill indications for CMR imaging according to the JACC White consensus paper.

All patients underwent biventricular EMB, cardiac catheterization for exclusion of coronary artery disease, and MRI on a 1.5 Tesla tomography (Intera, CV, Philips Medical Systems, Best, the Netherlands).

The CMR protocol included standard Lake-Louise (LL) parameters as well as native and post contrast T1 mapping using a modified Look-Locker inversion recovery sequence. Patients were divided into 2 groups according to duration of symptoms: patients with acute symptoms ≤14 days and those with chronic symptoms >14 days.

The diagnostic performance of LL criteria, native T1 and extracellular volume fraction (ECV) is summarized in the table. In patients with acute symptoms, native T1 yielded best diagnostic performance (81%) followed by ECV (75%), whereas accuracy of LL was found to be inadequate (60%). In patients with chronic symptoms, neither imaging technique or criteria yielded sufficient diagnostic accuracies.

Conclusion:
In patients with acute symptoms and suspected myocarditis, T1 mapping provides a useful tool for the confirming or rejecting the diagnosis of myocarditis and is superior to LL criteria. In contrast, native T1 and extracellular volume fraction demonstrated unsatisfying diagnostic accuracies in patients with chronic symptoms.