bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10246: Low Polygenic CAD Risk Score is Associated with Coronary Artery Calcium Score of Zero: A Real World Experience
Authors: Saad Shaukat Muhammad Hamza , Stys Veronica , stys patryk , Hajek Catherine , Petrasko Phillip , Pham Melissa , Rynders Beatrice , Petrasko Mark , Sjovold Alexander , Singh Komaldeep , Coy Kevin , Herman Michael , Sincan Murat , Stys Adam , Petrasko Marian S , Stys Tomasz P
Published: March 2022

Introduction:
Genetic predisposition for CAD is well established. Polygenic risk scores are emerging as tools to quantify the genomic component of an individual’s risk for CAD. However, their clinical utility for individual risk stratification is unclear.

Hypothesis:
180 SNPs previously identified in Caucasian Genome Wide-Association Studies for CAD were used to construct a weighted restricted polygenic risk score (PRS; normalized range 11.18 -17.58). This study hypothesizes that a low PRS (<85th percentile) is associated with coronary calcium score (CAC) of zero.

Methods:
Between January 2018 & March 2020, 21,784 patients underwent CAC screening and/or PRS testing. Caucasian patients with both PRS and CAC scores were identified. Fisher’s exact test was utilized to test the association between low PRS and CAC score of zero.

Results:
3,197 Caucasian patients had both PRS and CAC calculated, 1597 (49.9%) of whom had CAC greater than zero. Characteristics are summarized in table 1. Odds ratio of low PRS associated with CAC zero was 1.34 (95% CI 1.08 - 1.67; p=0.0079).

Conclusions:
In our Caucasian cohort, there is a statistically significant correlation between a low PRS and absence of coronary artery calcium. This is a real-world analysis incorporating genomic data for individual CAD risk stratification. Further studies on a larger, ethnically diverse cohort are needed.
Abstract 10248: Regulation of the Methylation and Expression Levels of the Bmpr2 Gene by Sin3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension
Authors: Bisserier Malik , Mathiyalagan Prabhu , zhang shihong , Elmastour Firas , Dorfmuller Peter , Humbert Marc , David Gregory , Weber Thomas , Perros Frederic , Sassi Yassine , Sahoo Susmita , Hadri Lahouaria
Published: March 2022

Background:
Epigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of Switch-Independent 3a (SIN3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH.

Methods:
We used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells (hPASMC). Expression of SIN3a was modulated using a lentiviral vector or a siRNA
in vitro
and a specific Adeno-Associated Virus serotype 1 (AAV1) or a lentivirus encoding for human SIN3a
in vivo
.

Results:
SIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. Interestingly, we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. Interestingly, SIN3a overexpression inhibited hPASMC proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 and EZH2 while promoting the expression of the DNA demethylase TET1. Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF binding to the BMPR2 promoter. Finally, we identified intratracheal delivery of AAV1.hSIN3a to be a beneficial therapeutic approach in PAH- by attenuating pulmonary vascular and RV remodeling, decreasing RVSP and mPAP pressure, and restoring BMPR2 expression in rodent models of PAH.

Conclusions:
Altogether, our study unveiled the protective/beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in hPASMC.
Abstract 10305: Cardiac Remodeling and Disease Progression in Patients with Repaired Coarctation of Aorta and Aortic Stenosis
Authors: Shaik Likhita , Devara Janaki , Katta Renuka Reddy , Iftikhar Momina , Goda Ahmed , Egbe Alexander C , Connolly Heidi M
Published: March 2022

Introduction:
Valvuloarterial impedance (Zva) is used for assessment of left ventricular (LV) global pressure load in patients with aortic stenosis (AS) and impaired arterial compliance. Since patients with coarctation of aorta (COA) have impaired arterial compliance, we hypothesized that COA patients with ≥moderate AS (AS-COA group) will have higher Zva, symptomatic progression, and cardiovascular events, as compared to non-COA patients with similar AS severity (AS group).

Methods:
1:1 propensity matching of 71 AS-COA and 71 AS patients based on age, sex, body mass index, and aortic valve mean gradient.

Results:
The AS-COA group had higher Zva (4.2±0.6 vs 3.5±0.4 mmHg/ml*m
2
, p<0.001), more advanced cardiac remodeling, and higher 5-year incidence of symptomatic progression (85% vs 51%, p<0.001). Pre-operative Zva was independently associated with cardiac remodeling (r=0.66, p<0.001) and symptomatic progression (HR 1.08, 1.05-1.12, per mmHg/ml*m
2
increase in Zva). Of 172 patients, 117 underwent aortic valve replacement (AVR). The AS-COA group had higher residual Zva(3.3±0.5 vs 2.4±0.4 mmHg/ml*m
2
, p<0.001), less robust LV mass index (LVMI) regression at 1-year post-AVR, and higher 5-year incidence of cardiovascular events. Post-operative Zva was independently associated with LVMI regression (r=-0.46, p<0.001) and cardiovascular events (HR 1.06, 1.02-1.10, per mmHg/ml*m
2
increase in Zva).

Conclusions:
Adults with repaired COA repair and moderate-severe AS had higher LV global pressure load, cardiac remodeling, symptomatic progression, and cardiovascular events as compared to non-COA patients with similar severity of AS. Zva can identify patients at risk for adverse outcomes, and perhaps should be used for risk stratification with regards to timing of AVR.
Abstract 10329: Health Status Outcomes of Percutaneous Coronary Intervention and Coronary Artery Bypass Grating in Stable Coronary Disease: Secondary Analysis of the ISCHEMIA Trial
Authors: Huded Chetan , Spertus John , Jones Philip , Mark Daniel B , Bangalore Sripal , Stone Gregg W , Ferguson T Bruce B , Williams David O , Boden William E , Reynolds Harmony , Hochman Judith S , Maron David J
Published: March 2022

Introduction:
In ISCHEMIA, participants (pts) with stable CAD and moderate/severe ischemia had better angina-related health status (symptoms, function, and quality of life) following an initial invasive strategy (INV), which could have been either PCI or CABG. In this analysis we describe the health status outcomes of INV pts, stratified by revascularization with PCI or CABG.

Methods:
We performed a descriptive analysis of unadjusted health status outcomes due to the non-randomized selection of PCI vs. CABG with inherent differences in groups. In 4617 out of 5179 pts in the trial, health status was assessed at baseline, 1.5 mos, 3 mos, 6 mos, and every 6 mos thereafter. The Seattle Angina Questionnaire (SAQ) summary score (SS) was the primary outcome, with higher scores indicating better health status.

Results:
Among 2295 INV pts with health status assessments,1257 underwent PCI and 350 CABG, while the remaining 688 were not revascularized within 3 mos. Initial conservative (CON) strategy was assigned in 2322 pts. Baseline SAQ SS was 72.1±19.2 in PCI, 73.4±17.8 in CABG, and 74.8±18.8 in CON groups. At 3 mos, SAQ SS was highest in PCI-treated pts (PCI 86.7±14.1, CABG 84.3±15.8, CON 81.8±17.0). Longer-term SAQ SS was consistently highest in CABG-treated pts at 1 year (Figure, PCI 87.5±14.8, CABG 89.8±13.2, CON 84.2±16.1), and 4 years (PCI 88.1±15.0, CABG 91.6±13.8, CON 86.9±15.4). Freedom from angina at 4 years was achieved in 75.9% of those treated with PCI, 82.8% with CABG, and 70.7% of CON pts.

Conclusions:
In this unadjusted non-randomized analysis from ISCHEMIA, those selected for PCI had the most favorable short-term health status, and those selected for CABG had the most favorable long-term health status. A fully risk-adjusted analysis is forthcoming to account for differences in patient selection and to facilitate between group comparisons.
Abstract 10369: Artificial Intelligence-Assisted Prediction of Blood Cells Regenerative Capacity in Patients with Diabetes Mellitus
Authors: Salybekov Amankeldi A , Buribayev Zholdas , Katsuaki Sakai , Yerkos Ainur , Natsumeda Makoto , Ikari Yuji , Kobayashi Shuzo , Asahara Takayuki
Published: March 2022

Introduction:
Peripheral blood mononuclear cell (PBMC) regenerative capacity is impaired in pre/diabetes mellitus patients (DMPs).
In vitro
evaluation of PBMCs pre/post vasculogenic conditioning (VC) and integrative assessment of classical clinical risk factors using complex machine learning-based (ML) methods may help to distinguish patients' immune cell regenerative potential.

Methods:
Eighteen DMPs diagnosed with myocardial infarction and sixteen controls were enrolled. Isolated PBMC regenerative capability was evaluated pre/post-VC using endothelial progenitor cell colony formation assay/unit (EPC-CFA/U) and flow cytometry analysis. The following classification ML algorithms were used for data analysis: support vector machine (SVM), logistic regression (LR), random forest (RF), decision tree (DT), and adaptive boosting (AB).

Results:
An
in vitro
EPC-CFA assay revealed that DMPs showed decreased fresh PBMC-derived definitive EPCs (DEPCs) compared with controls. Decreased colony formation was observed in patients with a reduced number of circulating EPCs and they did not appropriately respond to VC according to ML findings. Furthermore, proinflammatory M1 macrophages significantly increased (P = 0.03) in the majority of DMPs (non-responders) compared to that in controls, whereas VC shifted the phenotype toward M2 along with CD4
+
T and Treg cell expansion. Clinical, pre/post culture cell phenotype, and EPC-CFU data integration and comprehensive ML analyses distinguished “non-responder”-associated distinct biomarkers, clinical parameters, such as elevated proinflammatory cells and systemic inflammation, and elderly patients from those of responders. Notably, SVM prediction accuracy was 100%; both LR and RF were 86%; and those of AB and DT were 71% and 43%, respectively.

Conclusions:
Applying comprehensive ML methods, as well as integrative analysis of the findings of in vitro assays, such as EPC-CFA; such as EPCs, M1/M2 macrophages, and T cells pre/post-VC; and clinical-laboratory parameters, enabling us to precisely evaluate regeneration capacity of impaired PBMNC functions. Moreover, this cell culture methodology can be used before cell therapy to define optimal dose and cell ratio for transplantation.
Abstract 10425: Epigenetic Regulation of Notch Signaling by Prenatal Alcohol Exposure Impacts Cardiac Outflow Tract Defect Development
Authors: Harvey Drayton C , De Zoysa Prashan , Toubat Omar , Subramanyan Ram Kumar
Published: March 2022

Introduction:
Prenatal alcohol exposure (PAE) leads to congenital heart defects (CHD) with incomplete penetrance and phenotypic heterogeneity. We have demonstrated a gene-environment interaction in this context wherein acute PAE synergizes with second heart field (SHF) haploinsufficiency of Notch signaling, resulting in highly penetrant outflow tract (OFT) defects.

Hypothesis:
We hypothesize that acute PAE-induced hyperacetylation at histone marker 3 lysine residue 9 (aH3K9) epigenetically inhibits Notch signaling. This potentiates the impact of a pre-existing genetic defect that results in partial loss of Notch signaling leading to loss of viability of SHF progenitors necessary for OFT elongation and alignment.

Methods:
We studied the effects of acute PAE
in vivo
in our murine model (two injections of 3g/kg 30% ethanol on E6.5) on acetylation, SHF viability, OFT length, and Notch intracellular domain (NICD) localization. Complimentarily, we evaluated alcohol exposure
in vitro
using our established thoracic organ culture model. Acetylation was reversed using pan-histone acetyltransferase inhibitor anacardic acid.

Results:
At E9.5, acute PAE resulted in a significant increase in H3K9 acetylation in SHF associated with restriction of NICD to the cell membrane. This resulted in a 0.28-fold reduction in Notch signaling, as evidenced by reduced Notch reporter expression, and 0.52-fold reduction in SHF cell proliferation (both p<0.001). Loss of SHF progenitors needed for incorporation into the developing OFT reduced OFT length 26% (p<0.001).
In vitro
thoracic organ culture analyses recapitulated increased acetylation, NICD restriction to cell membrane and reduced SHF proliferation by 60% (p<0.001). Anacardic acid reversed the increase of aH3K9 and allowed NICD nuclear translocation. Notch signaling and SHF proliferation returned to baseline.

Conclusions:
Acute PAE induces hyperacetylation in the SHF and inhibits Notch signaling by restricting NICD translocation. Lack of Notch signaling reduces SHF viability and prevents elongation of the developing OFT. This hereto unexplored impact of alcohol on the Notch pathway provides a novel area of investigation regarding gene-environment interaction in alcohol teratogenesis.
Abstract 10461: Totum-854 Lowers Blood Pressure in L-NAME-Induced Arterial Hypertension in Mice and in Spontaneous Hypertensive Rat Model
Authors: Bolea Gaetan , Ripoche Doriane , MEYER Gregory , Le Joubioux Florian , Michaux Arnaud , OTERO Yolanda F , PELTIER Sébastien , SIRVENT Pascal , REBOUL Cyril
Published: March 2022

Introduction:
Arterial Hypertension (AHT) is a major cause of premature death worldwide. We have developed Totum-854 (T-854), a polyphenol-rich botanical composition to reduce the risk of developing AHT. We assessed the chronic effect of T-854 on preventing the development of L-NAME-induced AHT in mice, and the acute effect on blood pressure in spontaneous hypertensive rats (SHR).

Methods:
12-week-old C57Bl6/J mice were divided into Control, L-NAME, and L-NAME + T-854 group. L-NAME (100 mg/kg/day) was dissolved in drinking water. Mice received either T-854 (450 mg/kg) or vehicle by gavage once a day for three weeks
.
The arterial pressure was assessed using the CODA® Tail-Cuff System every week for three weeks. 12-week-old SHR rats received a dose of vehicle or T-854 (1250mg/kg) per os with a 48h-wash-out interval between two gavages, in random order. Arterial pressure was recorded during 24h post-gavage with a radio-telemetry device (HD-S10, DSI) directly implanted into the abdominal aorta.

Results:
In mice, L-NAME increased systolic (SBP; from 105±3 to 130±1 mmHg, p<0.0001), diastolic (DBP; from 77±3 to 97±2 mmHg, p<0.0001) and mean (MBP; from 86±3 to 108±2 mmHg, p<0.0001) blood pressure along the 3 weeks of treatment. Interestingly, in T-854-supplemented mice, SBP was significantly reduced from the first week of supplementation, and DBP and MBP from the second week of supplementation. After three weeks, T-854 lowered the SBP by 16% (p<0.0001), the DBP by 20% (p<0.05) and the MBP by 18 % (p<0.01), in comparison to L-NAME mice. In the SHR study, SBP and DBP were reduced during 24h recording after T-854 gavage in comparison to vehicle, with a 24h-AUC decreased by 108 ± 87.8 and 84.4 ± 69.3 mmHg.h, respectively.

Conclusions:
In conclusion, T-854 appears as an efficient strategy to prevent AHT and this effect was confirmed in two different preclinical models: L-NAME-induced AHT in mice and SHR rats.
Abstract 10482: Renin-Angiotensin-Aldosterone System Inhibition is Associated with Reduced In-Hospital Mortality in Critically Ill Covid-19 Patients with Pre-Existing Hypertension
Authors: Sato Kei , White Nicole , Fanning Jonathon P , Obonyo Nchafatso , Appadurai Vinesh , Ciullo Anna , May Meryta , Worku Elliott , Helms Leticia , Ohshimo Shinichiro , Yamashita Michael , Suen Jacky Y , Li Bassi Gianluigi , Fraser John F , ARORA Rakesh C ,   The COVID-19 Critical Care Consortium
Published: March 2022

Background:
The virus responsible for COVID-19 enters human cells by binding angiotensin-converting enzyme 2. The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), remains uncertain.

Aim:
To examine the role of ACEi / ARB exposure on outcomes in COVID-19 patients with pre-existing hypertension (HTN) admitted to intensive care units (ICU).

Methods:
The COVID-19 Critical Care Consortium is a prospective, observational cohort study of patients requiring ICU admission for active COVID-19 spanning 354 participating sites in 54 countries. Patients >18 years old with pre-existing HTN requiring antihypertensive therapy were analysed. Length of stay and in-hospital mortality to 90 days post ICU admission were analysed as time-to-event

outcomes by multistate survival analysis, and the influence of ACEi / ARB use on the hazards of death and discharge by multi-state Cox proportional hazard modelling and sensitivity analysis.

Results:
From December 1, 2019 through December 30, 2020, 663 eligible patients were registered. Of these, 480 patients had received ACEi and / or ARB therapy (median age 65 years, 67% male) in the 2 weeks before ICU admission, while 183 had not (66 years, 61% male). Average lengths of ICU and general ward stays were longer in the ACEi / ARB than non-ACEi / ARB group (20.8 days and 6.5 days vs. 15.5 and 6.0 days, respectively). ACEi / ARB use was associated with a decreased hazard of death (HR, 0.69, 95% CI, 0.54 — 0.88) that persisted after adjusting for propensity scores (0.67, 0.53 — 0.86). Cumulative probabilities (unadjusted for baseline characteristics) for death and discharge post ICU admission are depicted in the figure for ACEi/ARB (red) and non-ACEi / ARB (blue) patients.

Conclusions:
In 663 critically ill COVID-19 patients with pre-existing HTN, RAAS inhibition pre-ICU admission was linked to reduced in-hospital mortality.
Abstract 10491: CSL112 Suppresses Inflammation in Human Monocyte-Derived Macrophages
Authors: Didichenko Svetlana A , Adam Jacqueline , Navdaev Alexey V , Wong Mae , Alhamdoosh Monther , Saxenhofer Moritz , Velkoska Elena , Wright Samuel D , Kingwell Bronwyn A
Published: March 2022

Introduction:
Inflammatory monocytes and tissue-resident macrophages play a key role in the pathogenesis of atherosclerosis. Pro-inflammatory macrophages promote formation of unstable plaques whereas anti-inflammatory macrophages contribute to plaque stabilization. HDL (high-density lipoprotein) stimulates atherosclerosis regression in animal models and alters the inflammatory properties of monocyte-derived cells present in plaques. CSL112, human apoA-I formulated with phosphatidylcholine, is currently in a phase 3 clinical trial (AEGIS-II [ApoA-I Event Reducing in Ischemic Syndromes II]) to prevent major adverse cardiovascular events (MACE) in the 90-day high-risk period following myocardial infarction.

Objective:
To investigate the effects of CSL112 on human monocyte-macrophage differentiation and pro-inflammatory macrophage activation.

Methods:
Human blood monocytes from healthy donors were differentiated into macrophages in the absence or presence of CSL112, and then treated with/without the toll-like receptor 2/1 agonist P3CSK4. Gene expression analysis was performed using RNA sequencing technology; secreted cytokines were measured by ELISA.

Results:
CSL112 did not affect macrophage maturation or cause macrophage polarization towards the M1 or M2 phenotype in the absence of an inflammatory stimulus. After P3CSK4 stimulation, CSL112 exerted broad anti-inflammatory effects by significantly modulating the expression of multiple genes implicated in atherosclerosis. Specifically, CSL112 reduced gene and protein expression of CCL2, CCL4, TNFα and IL-6, decreased the expression of membrane bound receptor expressed on myeloid cells 1 (TREM-1) and inhibited the release of soluble TREM-1. Additionally, CSL112 suppressed P3CSK4-induced IL-18 secretion, while upregulated the expression of IL-18 binding protein, a natural antagonist of IL-18.

Conclusion:
Our findings demonstrate anti-inflammatory effects of CSL112 that may stabilize vulnerable atherosclerotic plaques and potentially contribute to reduction in MACE in the subacute period following myocardial infarction.
Abstract 10512: Sialic Acid-rich Fc Having A Strong Anti-inflammatory Effect In Kawasaki Disease Model
Authors: Yoshikane Yukako , Miyamoto Tatsuki , Koga Mitsuhisa , haraoka seiji , Cho Tamaki , Nagamitsu Shinichiro
Published: March 2022

Introduction:
Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery (CA) aneurysms. High-dose intravenous immunoglobulin (IVIG) is the most standard treatment. However, the problem with current high-dose IVIG therapy is that it is inefficient for both patients and cost because it contains ineffective parts and requires a high total dose. It has recently been reported that sialic acid in the fragment crystallizable (Fc) region has an anti-inflammatory effect.

Hypothesis:
In the KD model, a small amount of sialic acid-rich (SR-)Fc has an anti-inflammatory effect equivalent to that of high-dose IVIG.

Methods:
A
Candida albicans
cell wall extract (CAWE)-induced KD-like vasculitis model was established in DBA/2 mice. IgG, antigen-binding fragment (Fab), and Fc with 2g/kg/0.5ml, and IgG, SR-IgG, and SR-Fc with 0.2g/kg/0.5ml, and placebo 0.5ml were administered intraperitoneally 3 times every other day (n=5, respectively). Four weeks after treatment, we compared the incidence of CA inflammation between each group. Histological analysis was performed by using a quantified scoring system: grade 1; <20 cells /HPF, grade 2; <100cells/HPF, grade 3; >100cels/HPF, grade 4; distraction of elastic lamina, grade 5; neointimal proliferation.

Results:
All five mice in placebo group had the infiltration grade 3 or higher (100%), whereas none of the mice in IgG group had the infiltration (0%). In Fab group, three out of four had the infiltration (75%, one mouse died), whereas in Fc group, only one out of five had the infiltration (20%). In one-tenth dose IgG group, two out of four had the infiltration (50%, one mouse died), whereas in one-tenth dose SR-IgG and SR-Fc group, 20% or less of them had the infiltration (one out of five, zero out of five, respectively). Treatment with one-tenth dose SR-IgG and SR-Fc significantly suppressed CAWE-induced vasculitis (
p
<0.05 and 0.01, respectively).

Conclusions:
It was shown that the immunoglobulin effect was mainly in the Fc region and one-tenth dose SR-Fc had an anti-inflammatory effect equivalent to that of high-dose IgG in a
Candida
-induced KD mouse model. One-tenth doses SR-Fc may be an alternative treatment to high-dose IVIG in KD patients.
Abstract 10518: Impact of Managing Provider Type on Severe Aortic Stenosis Referral and Treatment Patterns: An Optum Electronic Medical Records Analysis
Authors: Pellikka Patricia A , Padang Ratnasari , Scott Christopher , Brinton Todd J , Murphy Shannon M , Fabunmi Rosalind , Thaden Jeremy J
Published: March 2022

A significant proportion of patients diagnosed with symptomatic severe aortic stenosis (ssAS) do not receive treatment with aortic valve replacement (AVR) despite current ACC/AHA guidelines. Delayed care leads to increased hospitalizations, worsening heart failure and death. Timely referral to a cardiac specialist is a critical step in the treatment pathway. We sought to identify the impact of managing provider type on follow-up care for newly diagnosed patients with severe aortic stenosis (sAS). We analyzed Optum® electronic medical records to identify adults with a new outpatient sAS echo diagnosis in the pre-COVID era (1/2017 - 3/2019). We identified integrated delivery network patients alive 1d post echo excluding those with missing data or AVR within 3d of echo, then selected those managed by a primary care provider (PCP) or a cardiologist (n=5,683). Baseline characteristics were used for covariate-adjusted Cumulative Incidence Function and Fine-Gray subdistribution hazard models. We estimated the impact of managing provider type on the specialist follow-up visit rate (cardiologist, interventional cardiologist and/or cardiothoracic surgeon) for all sAS patients and of surgical or transcatheter AVR for ssAS patients within 1 year of diagnosis. Within 90d of sAS diagnosis, 47% of PCP- vs. 73% of cardiologist-managed patients had a follow-up visit (1-year rates: PCP, 69% vs. cardiologist, 90%; Hazard ratio [HR]=0.54, 95% confidence interval [CI]: 0.49-0.59, p<0.0001). Within 1 year of diagnosis, 36% of PCP- vs. 51% of cardiologist-managed ssAS patients underwent AVR (HR=0.72, CI: 0.63-0.82, p<0.0001) (Figure). Analysis suggests lower referral rates for PCP- than cardiologist-managed patients. In ssAS, 1-year AVR rates were low, particularly for PCPs. These data underscore the importance of timely follow up of all severe AS patients for symptom assessment and appropriate treatment, presenting an opportunity for initiatives to drive behavior change.
Abstract 10544: A Gene Expression Signature Reflective of Exposure to Antiplatelet Therapy is Associated with Bleeding
Authors: Friede Kevin A , MYERS Rachel , Gales Jordan , Zhbannikov Ilya , Ortel Thomas , Shah Svati H , Kraus William E , Ginsburg Geoffrey S , Voora Deepak
Published: March 2022

Introduction:
Biosignatures composed of gene expression data hold promise for personalized antiplatelet therapy in conjunction with current guidelines and risk scores. The Aspirin Response Signature (ARS) of blood RNA transcripts is associated with lower platelet function after exposure to aspirin 325mg and increased risk of major adverse cardiovascular events (MACE). We studied a challenge cohort to determine if exposure to aspirin 81mg and ticagrelor changes ARS scores and a clinical cohort to determine whether ARS scores are associated with incident bleeding.

Methods:
Samples of whole blood and platelet-rich plasma (PRP) were collected from volunteers enrolled in a challenge study (N=188) who were sequentially exposed to 4 weeks of daily aspirin 81mg, then 325mg, then ticagrelor 90mg twice daily. ARS scores were calculated from whole blood RNA qPCR; platelet function and protein expression were assessed in PRP. ARS scores were also calculated in patients undergoing cardiac catheterization (N=1421).

Results:
In mixed models assessing the effect of antiplatelet drug exposure, exposure to aspirin 81mg was not associated with changes in ARS component gene expression or ARS score. Exposure to aspirin 325 mg resulted in an increase of 6.0% in aggregate ARS component gene expression (p<3x10
-4
vs baseline and vs aspirin 81mg) and an increase in expression of platelet proteins corresponding to ARS genes. Exposure to ticagrelor resulted in an increase of 30.7% in ARS component gene expression (p<1x10
-10
vs baseline and each aspirin dose) and ARS score (p<6x10
-4
vs baseline and each aspirin dose). In the catheterization cohort, 25.4% of patients experienced bleeding events over a median 6.2 years of follow up. In a Cox model adjusting for demographics and baseline antithrombotic medication use, patients with ARS scores above the median had a higher risk of incident bleeding (HR 1.26 [95% CI 1.01-1.56], p = 0.038).

Conclusions:
The ARS gene expression score increased in response to exposure to antiplatelet agents with different mechanisms of action in a dose- and potency-dependent fashion and was associated with increased bleeding risk. ARS scores could inform future strategies to individualize antiplatelet therapy to balance prevention of bleeding and MACE.
Abstract 10551: Management of Guideline-Directed Medical Therapy for Heart Failure in Office, Video and Telephone Outpatient Visits
Authors: Sammour Yasser , Main Michael L , Austin Bethany A , Magalski Anthony , Sperry Brett
Published: March 2022

Background:
There are limited data about management of guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF) with telehealth visits versus office visits. We sought to compare differences in the use of GDMT and loop diuretics between office, video, and telephone visits.

Methods:
We included 13,481 outpatient visits performed for 5,439 unique patients with HFrEF between March 16, 2020 and March 15, 2021. Multivariable logistic regression analysis was used to test differences between visit modes.

Results:
Overall, at least one GDMT class was started in 11.7% of office visits, 9.6% of video visits and 7.2% of telephone visits. Meanwhile, loop diuretics were initiated in 4.4% of office visits, 2.5% of video visits and 2.6% of telephone visits. After adjustment to baseline use of GDMT and loop diuretics, the rates of starting at least 1 GDMT class were similar between video and office visits (adjOR 0.95; 95% CI 0.82-1.12; p=0.558). There were no differences between video and office visits in discontinuing at least 1 GDMT class (adjOR 0.86; 0.71-1.04; p=0.119). Telephone visits were associated with less frequent initiation of at least 1 GDMT class compared with office visits (adjOR 0.77; 0.71-0.83; p<0.001), and video visits (adjOR 0.61; 0.51-0.74; p<0.001). Discontinuing at least 1 GDMT class during telephone visits was also less frequent than office visits (adjOR 0.91; 0.84-0.99; p=0.041), albeit similar to video visits. Compared with office visits, adding loop diuretics was less frequent with both video visits (adjOR 0.62; 0.47-0.83; p=0.001), and telephone visits (adjOR 0.62; 0.48-0.79; p<0.001) (
Figure
).

Conclusion:
The initiation of GDMT for HFrEF was similar between office and video visits, but lower with telephone visits, whereas the initiation of loop diuretics was lower with both video and telephone visits compared with office visits. These data can be useful when planning to augment GDMT in HFrEF using telehealth visits.
Abstract 10573: Dietary 7-Ketocholesterol Exacerbates Myocardial Ischemia-Reperfusion Injury Through Macrophage-Mediated Inflammation in Mice
Authors: Uchikawa Tomoki , Matoba Tetsuya , Katsuki Shunsuke , Koga Jun-ichiro , Tsutsui Hiroyuki
Published: March 2022

Background:
Myocardial ischemia-reperfusion (IR) injury limits the beneficial effects of early reperfusion therapy for acute myocardial infarction. Emerging evidence suggests that 7-ketocholesterol (7-KC), one of the most common dietary oxysterols, has pro-inflammatory properties and correlates with cardiovascular diseases. However, the underlying mechanisms remain scant. Here we investigated the effects of 7-KC on myocardial IR injury in mice.

Methods and Results:
Wild type mice were fed either a control high-fat high-cholesterol diet (HFHCD) or HFHCD containing 7-KC (7KC-HFHCD) for three weeks. In a murine model of 30-min myocardial ischemia and subsequent reperfusion, dietary 7KC-HFHCD increased plasma 7-KC level (145 ± 89.7 ng/mL vs 399 ± 175 ng/mL, P<0.0005, N=8) and infarct size after myocardial IR (52 ± 7.3% vs 64 ± 6.9%, P<0.05, N=8-10) without affecting blood pressure and heart rate. The ratio of Ly-6C
high
inflammatory monocytes to total monocytes increased in 7KC-HFHCD group as assessed by flow cytometric analysis (49 ± 15% vs 61 ± 9.3%, P<0.05, N=6). We then took a systems approach to explore the pro-inflammatory effects of 7-KC on macrophages and performed unbiased RNA-sequencing using murine peritoneal macrophages stimulated with 7-KC. Pathway analysis of differentially expressed transcripts revealed that 7-KC regulated the expression of transcripts related to inflammation, cholesterol biosynthesis and endoplasmic reticulum (ER) stress. We further validated
in vitro
that 7-KC induced ER stress, mitochondrial reactive oxygen species, and nuclear factor-kappa B activation associated with increased mRNA levels of pro-inflammatory cytokines such as MCP-1 and TNF-α in murine peritoneal macrophages. Administration of N-acetyl-L-cysteine (5mM), an antioxidant, decreased 7-KC-induced pro-inflammatory cytokines, and this decrease was not observed in
Tlr4
-/-
murine macrophages, or in macrophages transfected with liver X receptor siRNA.

Conclusions:
Dietary 7-KC exacerbated myocardial IR injury through macrophage-mediated inflammation in mice. Oxidative stress is involved in the 7-KC-induced pro-inflammatory response in macrophages. Dietary oxysterols are a promising therapeutic target for IR injury.
Abstract 10585: Racial Differences in Arterial Stiffness Following Acute Bouts of Anaerobic Exercise
Authors: Yan Huimin , Merchant Noelle , Bajdek Nicole
Published: March 2022

African Americans (AA) experience an exaggerated hemodynamic response during recovery from aerobic exercise compared to Caucasian Americans (CA). There is also evidence that local arterial stiffness increases and systemic vasculature stiffness decreases following aerobic exercise. Despite the growing popularity of high-intensity anaerobic exercise, no study has examined racial differences in arterial stiffness following maximal anaerobic exercise between AA and CA women.

Purpose:
To compare local and systemic arterial stiffness during recovery from repeated bouts of maximal anaerobic exercise in young, healthy AA and CA women.

Methods:
Twenty (AA: n=8, age = 22±1yrs, BMI = 24.7±0.8 kg/m
2
; CA: n=12, age = 22±1 yrs, BMI = 22.9 ±0.7 kg/m
2
) healthy women without hypertension completed two bouts of maximal anaerobic exercise on a cycle ergometer with 30 minutes of recovery between bouts. Hemodynamic measurements were taken at resting, and 5 (P5-post-EX1), 15 (P15 post-EX1), and 30 minutes (P30 post-EX1) following a maximal anaerobic exercise test on cycle ergometer, and 5 (P5 post-EX2), 15 (P15 post-EX2), and 30 (P30 post-EX2) minutes following the second maximal anaerobic exercise test. Local carotid arterial compliance (AC) was assessed using ultrasonography and systemic arterial stiffness was assessed by augmentation index (AIx@75) and segmental arterial stiffness assessed by central Pulse Wave Velocity (cPWV) using SphygmoCor. Data were analyzed by 2 by 7 (race *time) repeated measures ANOVA.

Results:
See Table 1.

Conclusion:
There is less variation in local carotid arterial compliance in AA women compared to CA women following repeated bouts of maximal anaerobic exercise despite similar systemic or segmental arterial stiffness. Racial differences in arterial distensibility between AA and CA women in response to maximal anaerobic exercise may be limited to localized changes in the predominantly elastic carotid artery.
Abstract 10604: Rs11091046-a Increases the Expression of Angiotensin Ii Receptor 2 Gene by Mir-208a
Authors: Zhao Liqun
Published: March 2022

Introduction:
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The mechanism of AF still remains unknown. In case - control study, we found that rs11091046 located in 3' - UTR of angiotensin II receptor 2 (AGTR2) gene was related to non - familial AF in Chinese Han population. It is necessary to figure out the mechanism of rs11091046 in non - familial AF.

Methods:
We predicted cohesion change between rs11091046 and miR-208a by RNAhybrid software and confirmed the prediction of cohesion change between rs11091046 and miR-208a by double luciferase reporter system. We detected the expression of AGTR2 gene in right atrium of patients with AF and subjects with sinus rhythm by quantitative real-time PCR.

Results:
RNAhybrid software showed that the cohesion between 3' - UTR of AGTR2 gene and seed region of miR - 208a was reduced because of the polymorphism of rs11091046 (wide type C mfe: -16.4kcal/mol, mutant type A mfe: -13.7kcal/mol). We also observed that the luciferase activity of transfected cells with miR - 208a and wild - type rs11091046 - C was significantly decreased by 59% while it was relatively enhanced by 22% with miR - 208a and mutant - type rs11091046 - A (Figure 1 up panel). The mRNA level of AGTR2 gene in right atrium of patients with AF was significantly increased compared with subjects with sinus rhythm. The mRNA level of AGTR2 gene in cardiomyocyte transfected by miR - 208a mimic was higher than cardiomyocyte transfected by miR - 208a (Figure 1 down panel).

Conclusion:
The polymorphism of rs11091046 in AGTR2 gene reduced the cohesion between 3 '- UTR of AGTR2 gene and seed region of miR - 208a, which increased the expression level of AGTR2 gene leading to occurrence of AF.

Figure 1 Up panel
The relative luciferase activity of transfected cells with wild - type rs11091046 - C and mutant - type rs11091046 - A (BK389: pmirGLO - rs11091046 - C, BK390: pmirGLO - rs11091046 - A). ** P < 0.01.
Down panel
The mRNA level of AGTR2 gene in cardiomyocyte transfected by miR - 208a mimic and miR - 208a. * P < 0.05.
Abstract 10690: Prevalence of Electronic Cigarette Use and Its Determinants in Us Persons of Hispanic Heritage: The Hispanic Community Health Study / Study of Latinos (HCHS/SOL)
Authors: April-Sanders Ayana K , Daviglus Martha L , Lee Un Jung , Perreira Krista , Pirzada Amber , Bandiera Frank , Giachello Aida L , Vu Thanhhuyen T , Rodriguez Carlos J
Published: March 2022

Introduction:
Popularity and use of electronic nicotine delivery systems (ENDS or e-cigarettes), have increased tremendously in the United States (US). Yet, data in a representative sample of US Hispanics/Latinos is limited. We determined the prevalence and correlates of ENDS use from the national Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Methods:
Cross-sectional data collected between the years 2015–2017 were analyzed to assess ENDS use (ever (current: use ≤ past 30 days; former: use > past 30 days) and never) among 11,623 adults aged 23+ years. Weighted prevalence estimates were reported and age-adjusted logistic regression models were used to examine associations between sociodemographic, lifestyle/behavioral, and clinical exposures with ENDS use (vs. nonsmokers and cigarette-only smokers, separately).

Results:
Mean age 47 years ± 0.3 and 52% women. The weighted prevalence of current and former ENDS use was 2.0% and 10.4%, respectively. Over 67% of current ENDS users reported dual-cigarette use. Current ENDS use prevalence estimates ranged from 1.1% in Hispanics/Latinos of South American background to 2.1% in Hispanics/Latinos of Mexican and Puerto Rican background. In logistic regression models, compared with nonsmokers, increased odds of current ENDS use was associated with males (OR=4.90, p<0.001), higher education (OR=2.03, p<0.05), English language preference (OR=7.59, p<0.001), Puerto Rican background (OR=2.09, p<0.05), a high level of physical activity (OR=4.02, p<0.001), and history of alcohol use (OR=15.93, p<0.001). Older age (≥45 years) (OR=0.30, p<0.001), foreign-born participants (OR=0.12, p<0.001), and those with obesity (OR=0.60, p<0.05) and type 2 diabetes (OR=0.46, p<0.001) had lower odds of current ENDS use. These trends were generally similar when cigarette-only smokers were the reference group. Having ever used ENDS was associated with prevalent coronary artery disease.

Conclusions:
Our study suggest that Hispanic/Latino individuals who are young adults, male, US-born, or have high acculturation are more likely to report current ENDS use.
Abstract 10698: Towards a Dialogue Agent to Assist African American and Hispanic/Latino Heart Failure Patients with Dietary Restrictions
Authors: Salunke Devika , Gupta Itika , Di Eugenio Barbara , Allen-Meares Paula G , Dickens Carolyn , Garcia Olga , Boyd Andrew D
Published: March 2022

Background:
Restricting dietary sodium is a common recommendation to address symptoms in heart failure (HF) patients. However, using the information provided on nutrition labels can be complex, leading to lapses in adherence. This problem is compounded by insufficient information on ethnic preferences in dietary habits. Based on our previous findings we developed a prototype dialogue agent (HF-DA) to assist African American (AA) and Hispanic Latino (H/L) patients with their HF self-care needs, including understanding nutrition labels and providing practical information per FDA recommendations.

Objective:
Compare HF-DA against existing technology in the public domain in assisting AA and H/L HF patients to make healthy food choices.

Methods:
We conducted a review of existing technology in two ways. 1: Google search engine: We measured the number of actions (typing, scrolling, clicking) required to find a source for a food’s sodium content matching the U.S. Department of Agriculture’s recommendations and used a calculator to understand the total sodium in a desired serving size. We identified relevant search terms by analyzing the commonly used words in the transcripts from our HF patient education sessions with their health educators (18 AA and 2 H/L) and 1:1 interviews with HF patients (3 AA and 1 H/L). 2: Google Play Store: We downloaded the top 15 apps using the search term “heart failure” and explored their functionality.

Results:
Google’s search engine required users to perform 1 action to identify the sodium content and percent daily value but then needed 6-8 actions (dependent on query length) to calculate sodium content of total serving size. Our HF-DA provides this information in 4 actions. Of the 15 apps available in the Play Store, none had any features for understanding nutrition labels.

Conclusion:
Our preliminary analysis revealed there are very few culturally sensitive technological resources available to assist HF patients in understanding nutrition labels. These resources require a patient to understand nutrition labels, perform arithmetic, and recall dietary restrictions. HF-DA is capable of promoting healthy eating habits by aiding HF patients' decision-making process by providing reliable information in fewer steps.
Abstract 10699: Predictors of Health Activation in Rural Caregivers with Multiple Cardiovascular Disease Risks
Authors: Chung Misook L , Cha Geunyeong , Lin Chin-Yen , Miller Jennifer , Lennie Terry A , Rayens Mary Kay , Feltner Frances J , Moser Debra K
Published: March 2022

Introduction:
Caregivers of patients with chronic conditions are at higher risk for cardiovascular disease (CVD) than their urban counterparts. Despite the burden related to caregiving, caregivers need to be activated for their own health to decrease this risk. Health activation has not been studied in rural caregivers. It is particularly relevant because most rural dwellers live in low-resourced, socioeconomically distressed environments where their health activation may be challenging. The purpose of this study was to identify characteristics of rural caregivers with multiple CVD risk factors who were not considered “activated” in their own health.

Methods:
Rural caregivers who had at least two CVD risk factors completed surveys on caregiver burden (Zarit Burden Interview), adherence to a healthy lifestyle (MOS Specifical Adherence Scale), perceived health status, and caregiving characteristics, and we calculated the Framingham CVD risk score. Health activation was assessed using the Patient Activation Measure, which categorizes people into four categories: overwhelmed, struggling, taking action, and maintaining levels. A multi-nominal logistic regression model was used to determine predictors of patient activation category.

Results:
Of the total of 269 rural caregivers (mean age= 54.1 years, 78% female), 36% were in the maintaining level, 42% were in the taking action level, and 22% in overwhelmed/struggling level. There were no significant differences in demographic or caregiving characteristics among the groups. Compared to the maintaining group, caregivers who had high caregiving burden (OR = 1.035, P = .007) and high Framingham CVD risk (OR = 1.061, P = .025), and low adherence to healthy behavior (OR = .917, P < .001) were more likely to be in the overwhelmed/struggling group. Caregivers who had a high burden (OR = 1.026, P = .012) and low adherence to healthy behaviors (OR = .926, P < .001) were more likely to be in the taking action group.

Conclusions:
Most rural caregivers were not activated on their health management even though they have multiple CVD risk factors. Screening health activation levels are needed for caregivers, and developing tailored intervention based on activation levels is needed.
Abstract 10701: Suspension Differentiation of Cardiomyocyte Spheroids Improves Quality and Yields
Authors: Kahn-krell Asher , Pretorius Danielle , Ou Jianfa , Litovsky Silvio , Liu Margaret , Zhang Jianyi
Published: March 2022

Introduction:
Improvements in stem cell viability, differentiation efficiency, and functional activity opened the door for advanced research applications in cardiac regeneration. However, the use of cell-based cardiac therapies, including implantable patches and cell products as well as in-vitro models for mechanistic studies and drug development requires large numbers of high-quality cardiomyocytes (CMs). Typically, differentiation is conducted in 6-well culture plates via the GiWi method, which uses small-molecule inhibitors of glycogen synthase kinase (GSK) and tankyrase to first activate and then suppress Wnt signaling. This monolayer method requires significant manual labor and cannot be easily scaled. Suspension culture and differentiation of free-floating hiPSC aggregates following similar biochemical cues offers advantages for commercial biomanufacturing purposes and provides a more physiological environment for cell development.

Hypothesis:
We assessed the hypothesis that when hiPSCs are cultured and differentiated in suspension they will produce CMs with improved yield, purity, and quality.

Methods:
hiPSCs were expanded as aggregates in culture flask using a fed-batch approach then differentiated over a 12 day period with Wnt activation on day 0 and inhibition on day 3. Optimization studies examined purity on day 9 and complete characterization via morphological assessments and CM-specific genes expression was done on day 12 following metabolic purification. All studies were conducted with a minimum of 4 replicates.

Results:
Optimal conditions for both purity and yield based on cardiac troponin T staining were achieved with an initial cell density of 1.6x10
6
cells/mL, 6 μM CHIR99021, and 55 rpm shaking. After scaling to 30mL culture volume the purity of hiPSC-CMs differentiated via our novel protocol was 98.2±0.8% with yields of 1.47±0.18 million cells/mL and less between-batch purity variability than hiPSC-CMs produced in 2D cultures.

Conclusions:
Suspension differentiation of hiPSCs into CMs in a widely available format results in improved biomanufacturing endpoints. Therefore, this method functions as a groundwork for future bioreactor systems to produce the large number of cells needed for clinical applications.