bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13202:
LncRNA-MAP3K4
Regulates Vascular Inflammation Through a P38 MAPK Signaling Pathway and
Cis
-modulation of MAP3K4
Authors: Zhou HaoYang , Simion Viorel , Pierce Jacob , Feinberg Mark W
Published: November 2020

Introduction:
Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in vascular inflammation remains poorly understood.

Hypothesis:
Identification of inflammation-responsive lncRNAs expressed in the aortic intima may provide novel mechanistic insights in vascular inflammation.

Methods:
Using RNA-Seq profiling to identify a lncRNA derived specifically from the aortic intima of atherosclerotic mice, we discovered an inflammation-responsive lncRNA,
lncRNA-MAP3K4,
and evaluated its role in the mechanisms mediating vascular cell inflammation.

Results:
Aortic expression of
lncRNA-MAP3K4
, an intima-enriched and polyadenylated lncRNA
,
was reduced by 50% with atherosclerotic progression and by 75% following LPS-induced endotoxemia in mice. GapmeR-mediated silencing of
lncRNA-MAP3K4
potently reduced mRNA and protein expression of adhesion molecules or chemokines (e.g. ICAM-1, E-selectin, MCP-1) in endothelial cells via a p38-MAPK pathway, and decreased PBMC adhesion to endothelium by 40%. Moreover,
lncRNA-MAP3K4
knockdown also reduced inflammatory markers in vascular smooth muscle cells and macrophages. Analyzing the
lncRNA-MAP3K4
locus, we found MAP3K4, an upstream kinase of the MAPK cascade, shared the promoter region with
lncRNA-MAP3K4. In vitro
and
in vivo, lncRNA-MAP3K4
and MAP3K4 showed parallel inflammation-responsive expression patterns.
lncRNA-MAP3K4
knockdown reduced mRNA and protein expression of MAP3K4 in
cis
in vessel wall cell types. ChIP-seq data showed chromatin modifications and bidirectional promoter characteristics in the
lncRNA-MAP3K4/
MAP3K4 promoter region. MAP3K4 knockdown showed a similar anti-inflammation phenotype as
lncRNA-MAP3K4
via a p38-MAPK pathway and cooperativity with
lncRNA-MAP3K4
.

Conclusions:
Deficiency of
lncRNA-MAP3K4
markedly reduced inflammation in vascular cells via a p38-MAPK pathway and
cis
-regulation of MAP3K4 from a shared bidirectional promoter. This study illustrated a divergently transcribed lncRNA/protein-coding gene pair involved in vascular inflammation and more broadly informs a better understanding of mammalian genome regulatory mechanisms in vascular disease states.
Abstract 13208: Pedal Arterial Calcification Score Correlates With Risk of Death and Major Adverse Cardiovascular Event in Patients With Chronic Limb Threatening Ischemia
Authors: Liu Iris H , Wu Bian , Krepkiy Viktoriya , ferraresi roberto , Reyzelman Alexander , Hiramoto Jade S , Schneider Peter A , Conte Michael S , Vartanian Shant M
Published: November 2020

Introduction:
Peripheral arterial disease is associated with cardiovascular morbidity and mortality, and the burden of PAD can be used to reclassify risk within CVD models. We describe a novel, practical score for quantifying peripheral arterial calcification based on plain x-ray films of the foot (MAC). We hypothesize that high MAC score is associated with risk of death and major adverse cardiovascular events (MACE; defined as MI, coronary intervention, CVA, TIA) in patients with chronic limb-threatening ischemia (CLTI).

Methods:
This is a single-institution retrospective study of 275 patients who underwent infrainguinal revascularization for CLTI between 1/2011 and 7/2019. MAC scores were calculated by a single blinded reviewer using two-view plain foot radiographs. Each patient was assigned a score of 0-5, with 1 point each for calcifications > 2 cm in the dorsalis pedis, plantar and metatarsal arteries, and > 1 cm in the hallux and non-hallux digital arteries.

Results:
The distribution of MAC scores was 0 (45%), 1 (4.7%), 2 (8.4%), 3 (18%), 4 (12%) and 5 (11%). MAC scores were trichotomized [mild (0-2), moderate (3-4), severe (5)] and higher scores were associated with male sex, DM, ESRD, and history of smoking. Median follow-up was 620 days (IQR 263-1494). Higher MAC score was significantly associated with MACE (p=0.01) and all-cause mortality (p=0.03), and was predictive of worse MACE-free survival (MACEFS; p=0.01;
Figure 1
). In a Cox Proportional Hazards model for MACEFS that included age; ESRD; CAD; history of CVA or TIA; Society for Vascular Surgery Wound, Ischemia and foot Infection (WIfI) stage; and MAC; the most severe MAC score (HR 1.8 [1.01-3.4] for MAC 5, p=0.04) was significantly associated with worse MACEFS.

Conclusions:
The MAC score is an independent predictor of MACE-free survival in patients with CLTI. It is a simple, quick and inexpensive tool that has the potential to stratify patients at highest risk of long-term cardiovascular complications.
Abstract 13215: Gender-affirming Hormones Are Associated With Increased Risk of QT Prolongation in Transgender Females
Authors: Antwi Amoabeng Daniel , Hanfy Ahmed , Awad Munadel , Beutler Bryce D , Rai Amneet , Gbadebo David T , Keogh Michael
Published: November 2020

Introduction:
Women have a longer QT interval than men. This sex-specific difference is attributed to hormones associated with the biological female sex. Male-to-female transgender individuals often take antiandrogens such as spironolactone or goserelin in addition to estrogens to suppress testosterone effects while increasing feminine features. Effects of gender-affirming hormone therapy (GHT) on the QT interval in these individuals remains to be elucidated.

Hypothesis:
We assessed the hypothesis that the use of GHT is associated with an increased risk for QT interval prolongation in transgender females.

Methods:
We identified 46 transgender females through a search of the electronic medical records of a Veterans Administration hospital in Northern Nevada. Patients with a diagnosis of congenital long QT syndrome were excluded. Of these, 13 patients had ECGs before and after initiation of GHT and were included. We adapted the Tisdale score using the auto-calculated corrected QT interval (QTc) to estimate the risk of QT prolongation. Age, QTc, and Tisdale scores before and after GHT initiation were compared using the Wilcoxon signed-rank test. All tests were performed as two-tailed at a 5% level of significance.

Results:
All 13 study patients were taking estrogens. Of these, 3 (23.1%) were taking goserelin and 9 (69.2%) were taking spironolactone. Mean ± SEM age at ECG acquisition was 45.0 ± 4.4 and 47.7 ± 4.7 years before and after the initiation of GHT respectively. Mean ± SEM QTc after initiation of GHT was significantly higher compared to the baseline (467.5 ± 12.8 ms vs. 428.2 ± 7.1 ms) (Figure 1A). The average baseline Tisdale score was significantly smaller on follow-up (1-point vs. 3 points) (Figure 1B).

Conclusions:
GHT appears to be associated with increased QTc in transgender women. This needs to be interpreted with caution owing to the very small sample size in this study. Further studies to investigate the strength of this association, if it exists, are warranted.
Abstract 13276: Dyad Gender and Relationship Quality Are Related to Heart Failure Self-care Maintenance
Authors: Stawnychy Michael A , Vellone Ercole , Zeffiro Valentina , Riegel Barbara J
Published: November 2020

Background:
Self-care, a process of health maintenance, monitoring and symptom management, improves morbidity and mortality in adults with HF. Caregivers are important in promoting patient self-care but little is known about the effect of relationship quality (RQ) on HF patient self-care, especially in same and mixed gender dyads.

Aim:
Quantify the contribution of dyadic gender and RQ on HF patient self-care maintenance.

Methods:
Secondary analysis of baseline data from a study of Italian adults with HF and their caregivers (
n
=503). Dyads were enrolled to assess effectiveness of motivational interviewing on HF self-care maintenance measured with the Self-Care of Heart Failure Index v.6.2, validated in an Italian population. RQ was assessed with the Mutuality Scale, validated for HF patients and caregivers. Dyadic gender was categorized as Male-Male (M-M), Female-Male (Fpt-Mcg), Female-Female (F-F), and Male-Female (Mpt-Fcg; reference group). Univariate linear regression with backward elimination (
p
<.05) was used to identify determinants of HF patient self-care maintenance.

Results:
The sample was 48% Mpt-Fcg, 27% F-F, 15% Fpt-Mcg, 10% M-M. Mpt-Fcg dyad patients were married (86%); with older (59±15 years), less educated (46% secondary or lower) spousal caregivers (66%). More F-F vs M-M patients lived alone (32% vs 4%). Determinants of better patient self-care were: living alone, receiving assistance for HF, better mental quality of life, patient and caregiver employment, caregiver married status, higher caregiver perceived social support, and more months caring for the patient. Dyad gender, RQ, and these covariates explained 23% of variance in patient self-care maintenance. Dyad gender independently contributed to self-care, but only for same gender dyads. Being in a M-M dyad was associated with higher patient self-care (ß=.52,
p
<.026). Better caregiver perception of RQ in both M-M and F-F dyads was associated with lower patient self-care (M-M: ß=-.97,
p
<.001; F-F: ß=-.55,
p
<.026). There were no significant interactions for patient RQ or mixed gender dyads.

Conclusion:
Dyadic relationship quality appears to be important for self-care, particularly in M-M dyads and should to be considered when working with HF patients and their caregivers.
Abstract 13284: Cardiac Rehabilitation, Cardiorespiratory Fitness, and Risk of Incident Atrial Fibrillation in Patients With Coronary Artery Disease
Authors: Liu Hongwei , Southern Danielle A , Arena Ross , Sajobi Tolulope , Aggarwal Sandeep , Wilton Stephen
Published: November 2020

Introduction:
Cardiorespiratory fitness (CRF) is an independent risk factor for cardiovascular morbidity and mortality. Cardiac rehabilitation (CR) can reduce cardiovascular risk factors and improve CRF. However, the relationship between CR, CRF, and risk of incident atrial fibrillation (AF) in patients with cardiovascular disease is less clear.

Objectives:
To examine the association of CR completion and associated CRF changes with the incidence of new-onset AF in patients referred to a CR program after coronary revascularization.

Methods and Results:
We included 11,662 patients without a history of AF, referred to CR after coronary revascularization between January 1996 to March 2016. The mean age was 60.9 ± 10.9 years and 80.6% were males. Incident AF was ascertained by linkage with provincial administrative data sources and the local ECG repository. Competing-risks regression was used to estimate the association of CR completion and CRF with incident AF, with death as a competing event. During a median follow-up of 4.8 years, 618 patients developed AF, and 638 died. In adjusted models, CR completion was not associated with the risk of incident AF [Hazard ratio (HR): 0.97; 95% confidence interval (CI): 0.83-1.15]. However, both baseline CRF [HR: 0.83; 95% CI: 0.76-0.90 per metabolic equivalent (MET)] and CRF gain (HR: 0.82; 95% CI: 0.72-0.94 per MET increase) for those who completed the CR program were associated with a lower risk of incident AF (Table 1).

Conclusions:
In patients referred to CR, CR completion was not associated with a reduced risk of incident AF. However, both higher baseline CRF and CR-associated CRF gains had a dose-dependent protective association with incident AF. Therefore, it is important to maximize CRF gains during the CR program. Further attention to AF-specific risk factor modification (i.e., obesity, sleep apnea, and alcohol) may be required to enhance CR program efficacy for this outcome, especially in patients with lower baseline CRF.
Abstract 13287: The Clinical Value of Serum Albumin in Predicting Long-term Bleeding Events in Patients Who Underwent Percutaneous Coronary Intervention
Authors: Ando Takuya , Shimizu Takeshi , Akama Joh , Anzai Fumiya , Muto Yuuki , KIMISHIMA Yusuke , Kiko Takatoyo , YOSHIHISA Akiomi , Yamaki Takayoshi , Kunii Hiroyuki , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika
Published: November 2020

Background:
It has been known that East Asian people, including Japanese, has a high bleeding risk (HBR) than Western. Therefore, risk stratification is important to detect HBR patients among patients who underwent percutaneous coronary intervention (PCI). The aim of the present study was to investigate the association between serum albumin level and bleeding events in patients who underwent PCI.

Methods and Results:
Consecutive 1027 patients who underwent PCI and had been discharged from our institution were enrolled. We divided the patients into three groups based on serum albumin levels at discharge: the first tertile (≤3.7 g/dL, n=358), second tertile (3.8-4.1 g/dL, n=308) and third tertile (≥4.2 g/dL, n=361). Clinical characteristics of three groups were as follows: mean age (the first, second and third tertile; 72.9, 69.3 and 63.4 years, P<0.001), body mass index (23.4, 24.4 and 24.9 kg/m
2
, P<0.001), prevalence of male sex (70.7%, 78.6% and 87.1%, P<0.001), chronic kidney disease (53.8%, 39.3% and 27.1%, P<0.001), anemia (27.9%, 11.3% and 7.2%, P<0.001), atrial fibrillation (21.2%, 12.0% and 11.6%, P<0.001), peripheral artery disease (16.5%, 12.5% and 8.8%, P=0.021), stroke (23.2%, 17.9% and 9.6%, P<0.001), heart failure (54.1%, 28.1% and 21.7%, P<0.001), and use of anticoagulants (17.3%, 10.0% and 10.7%, P=0.007). In contrast, combination of antiplatelets did not differ among groups. In the Kaplan-Meier analysis (mean follow-up 1742 days), accumulated bleeding events progressively increased from the third tertile to the first tertile (Figure). The multivariable Cox proportional hazard analysis revealed that the first tertile (vs. third tertile) was independently associated with bleeding events in patients who underwent PCI (hazard ratio 3.080, 95% confidence interval 1.362-6.961, P=0.007).

Conclusion:
In patients who underwent PCI, low serum albumin level is independently associated with long-term bleeding events.
Abstract 13295: Novel Experimental Therapeutics for COVID-19 Derived From a Nitric Oxide Donor
Authors: Schmedtje John F , Assar Zahra
Published: November 2020

Urea transport protein B, the product of the gene
SLC14A1
, facilitates transport of urea, water and urea analogues across cell membranes.
SLC14A1
mRNA is overexpressed in human vascular endothelial cells in culture under hypoxic (1% oxygen) conditions compared with normoxia. This leads to transport of urea out of the endothelial cell and likely contributes to the reduction in eNOS (endothelial nitric oxide synthase) pathway activity in hypoxia. NO has antiviral activity. Novel compounds were developed by binding a urea-like moiety to the backbone of the generic agent isosorbide mononitrate, a well-known NO donor, to combat vascular endothelial dysfunction in COVID-19, a disease characterized by systemic hypoxia and inflammation due to SARS-CoV-2 infection. A study of drug-protein interactions was undertaken using
in silico
modelling. Novel compounds were studied against 9 key SARS-CoV-2 targets using Maestro, Schrödinger Suite software (Glide docking). Docking scores and intermolecular interactions within the target’s key binding amino acid residues were studied to compare investigational compounds and known antivirals. Several novel agents tested had a better Glide Score (a prediction of ligand affinity) against the papain-like protease (PL
pro
) of SARS-CoV-2 compared with known antiviral drugs. PL
pro
is considered to be a primary target for therapeutic inhibition of the SARS viruses. The candidate compounds CR-305, CR-607, CR-510 and CR-605 were all superior to Remdesivir, GS-441524, Lopinavir, Boceprevir, and Ribavirin. Given the known direct antiviral action of NO and evidence of specific binding of these compounds to the PL
pro
of SARS-CoV-2 based on the
in silico
results, we conclude there is a high likelihood these novel compounds will prove to be of therapeutic value against COVID-19. CR-305 appears to have a higher affinity to SARS-CoV-2 than other antivirals as it sits firmly in the PL
pro
catalytic pocket and makes the most of key interactions with the catalytic pocket residues: Gly163, Asp164, Gln271 and Tyr264. These data call for a new focus on these novel antiviral agents as they appear to bind with an increased avidity to PL
pro
(compared with other known antivirals) while targeting delivery of NO to the SARS-CoV-2 virus in COVID-19.
Abstract 13296: Risk Loci of Hypertrophic Cardiomyopathy Identified via the UK Biobank
Authors: Gyftopoulos Alex , Chen Yi-Ju , Wang Libin , Williams Charles H , Chun Young Wook , Perry James A , Hong Charles C
Published: November 2020

Introduction:
Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiac disease affecting 1:500 to 1:200 individuals worldwide. HCM has a heterogeneous genetic profile and phenotypic expression. More than 1400 known pathogenic variants have been identified in 11 sarcomere genes. In about 40% of HCM patients, the genetic cause may not be identified. The same mutation may lead to different phenotypes and severity in different individuals. Identification of novel HCM genes and modifiers will expand our understanding of the signaling pathways that are responsible for phenotypic expression of HCM.

Methods:
The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals. We used OASIS, an information system for analyzing, searching, and visualizing associations between phenotype and genotype data to analyze this data. We compared control individuals to HCM individuals identified by ICD-10 code (I42.1 and I42.2) in a 20-to-1 fashion. Related individuals and those with confounding diagnoses were excluded.

Results:
The analysis was performed with Plink’s GLM option, and we identified 84 variants with a minor allele frequency of 0.5% or greater in 65 genes associated with HCM with a
p
< 1x10
-6
, including 4 with
p
< 5x10
-8
. The identified genes encode lncRNAs, miRNAs, and membrane proteins. Variants with high significance were identified in the genes encoding putative ciliary components
DNAL4
(dynein axonemal light chain 4;
p
= 2.9x10
-8
),
MYO1D
(unconventional myosin 1D;
p
= 3.1x10
-8
),
ITFAP
(intraflagellar transport associated protein;
p
= 9.5x10
-8
),
CABCOCO1
(ciliary associated calcium biding coiled-coil 1;
p
= 3.7x 10
-7
),
EVL
(Enah-Vasp-like;
p
= 4.4x 10
-7
) and
IFT122
(intraflagellar transport 122;
p
= 8.0 x10
-7
).

Conclusion:
While none of these have previously associated with HCM, our findings suggest ciliary structure and function may play a role in disease manifestation. Our method is unique by pooling individuals in a large population set to identify potential causative or contributing mutations. Bioinformatic tools, such as OASIS, allow for the identification of previously unrecognized variants that may play a role in the development of HCM. This approach has identified numerous novel genes as possible risk loci.
Abstract 13610: Endothelial Cu Transporter Atp7a Promotes Vegfr2 Signaling and Post-ischemic Neovascularization via Regulating Autophagy
Authors: Ash Dipankar , Varadarajan Sudhahar , Youn Seock-Won , Okur Mustafa N , O'Brien John P , McMenamin Malgorzata , Fang Xuexiu , Hou Yali , Kaplan Jack , Fukai Tohru , Ushio-fukai Masuko
Published: November 2020

Background:
VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role in angiogenesis. Copper (Cu) is essential micronutrient and has been implicated in angiogenesis. The P-type ATPase transporter ATP7A is key regulator of Cu homeostasis but its role in VEGFR2 signaling in ECs and post-ischemic neovascularization is entirely unknown.

Results:
Here we show that ATP7A expression was dramatically increased in the angiogenic ECs in mice hindlimb ischemia model. EC-specific ATP7A deficient mice or Cu transporter-dysfunctional ATP7A
mut
mice showed significant decrease in blood flow recovery and CD31+ capillary density (angiogenesis) in ischemic tissues compared to their control mice. In cultured human ECs, ATP7A knockdown with siRNA significantly inhibited VEGF-induced migration (67%), capillary network formation on Matrigel (46%). Immunofluorescence, co-immunoprecipitation, and proximity ligation assays showed that VEGF stimulated ATP7A translocation from the trans-Golgi network to the plasma membrane where it bound to VEGFR2. Surprisingly, loss of ATP7A promoted VEGF-induced VEGFR2 protein degradation (56%) and inhibited VEGFR2 signaling via enhancing VEGFR2 ubiquitination (2.0-fold) in a Cu-independent manner. This was associated with reduced cell surface VEGFR2 expression, increased VEGFR2 binding to selective autophagic cargo/adaptor p62/SQSTM1 (60%) and LC3-GFP+autophagic puncta (34%) and autolysosome formation (transmission electron microscopy). Inhibition of autophagy by bafilomycin A1 or chloroquine prevented enhanced VEGFR2 degradation in ATP7A-depleted ECs. Furthermore, overexpression of p62, but not p62 lacking ubiquitin binding domain, or autophagy inducer rapamycin treatment increased VEGFR2 degradation (26% and 87%, respectively) and p62 overexpression inhibited ECs migration (29%). Enhanced autophagy flux due to ATP7A dysfunction
in vivo
was confirmed by employing autophagy reporter CAG-ATP7A
mut
-RFP-EGFP-LC3 transgenic mice.

Conclusion:
Our study uncovers the unexpected and novel function of ATP7A to limit autophagic degradation of VEGFR2, thereby promoting VEGFR2 signaling and angiogenesis, which restores neovascularization in ischemic disease.
Abstract 13615: Weekdays versus Weekends: Outcomes of Cardiogenic Shock in the Setting of Acute Myocardial Infarction
Authors: Moreyra Abel E , Vakil Deep , Zinonos Stavros , Cosgrove Nora M , Kostis John B , Kostis William J ,   for the MIDAS study group
Published: November 2020

Introduction:
Acute myocardial infarction (AMI) accounts for the majority of patients with cardiogenic shock (CS). The high case fatality justifies the need for an optimal hospital care system that is available 24 hours, 7 days a week. It is unclear whether the “weekend effect” has an impact on the outcome of CS associated with AMI.

Hypothesis:
Weekend CS-AMI admissions have a higher in-hospital case fatality than weekday admissions.

Methods:
A total of 22,632 patients with ST segment elevation AMI complicated with CS between the years 1986 to 2015 were identified in the Myocardial Infarction Data Acquisition System, a statewide database of all admissions to non-federal hospitals in NJ. Trend analysis was performed using a logistic regression model with admission year as a continuous variable. Case fatality rates between weekend vs weekday admissions were compared using the Cochran–Mantel–Haenszel test, stratifying by admission year.

Results:
From 1986 to 2015 there was a steady decline in the rates of in-hospital case fatality of AMI complicated with CS, from 79% to 33% (p< 0.001). The overall CS death rate for admissions on weekends was 61% and for weekdays 59% (Common-Odds Ratio = 1.10 (95% CI (1.02-1.17) p= 0.006) (figure). The use of mechanical circulatory support (MCS) was lower on weekends (p<0.001) and was associated with a higher case fatality rate 48 hours from admission (p<0.001).

Conclusion:
Deaths related to CS complicating AMI have steadily declined and this applies for both, patients admitted on weekends and weekdays. There was a higher hospital death rate in patients admitted over weekends compared to weekdays. The underutilization of MCS devices during weekends likely contributes to the difference in case fatality between weekends and weekdays.
Abstract 13625: Effect of Empagliflozin versus Placebo on Plasma Volume Status in Patients With Acute Myocardial Infarction and Type 2 Diabetes Mellitus: Subgroup Analysis of the Embody Trial
Authors: Hoshika Yu , Kubota Yoshiaki , Mozawa Kosuke , Tara Shuhei , Tokita Yukichi , Yodogawa Kenji , Iwasaki Yuki , Yamamoto Takeshi , Takano Hitoshi , Tsukada Yayoi , Asai Kuniya , Miyamoto Masaaki , Miyauchi Yasushi , Kodani Eitaro , Maruyama Mitsunori , Tanabe Jun , Shimizu Wataru
Published: November 2020

Background:
Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been evaluated recently as a prognostic marker of patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor affect the improvement of heart failure and PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF).

Methods:
The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of the SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. A total of one hundred and five patients were randomized (1:1) to receive once-daily 10 mg empagliflozin or placebo 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS on baseline, weeks 4, 12 and 24.

Results:
Overall, 96 patients were included in the subgroup analysis set (64.3±10.9 years, male 80.2%, and 46 in the empagliflozin group and 50 in the placebo group). The empagliflozin group showed significant decreases in body weight, systolic blood pressure, and PVS compared with the placebo group at 24 weeks (-2.2 vs. +0.1 kg, P=0.0007; -6.6 vs. +3.5 mmHg, P=0.003; and -5.1 vs. -0.3%, P=0.0006; respectively). Decreased of PVS, defined as change of PVS < -4.5 % was associated with received empagliflozin (odds ratio, 2.61; 95% confidence interval, 1.11 - 6.15; P=0.028). On the other hand, NT-Pro BNP levels significantly decreased in the empagliflozin group and placebo group (1028.7 to 370.3 pg/ml, P=0.0001 and 1270.6 to 673.7 pg/ml, P=0.006, respectively).

Conclusion:
Empagliflozin reduced not only body weight but also PVS. These results suggested that early SGLT2 inhibitor administration in patients with AMI, CHF and T2DM could be effective to reduce body weight and PVS.
Abstract 13626: Human Leukocyte Antigen A*30 is Associated With Congenital Heart Disease
Authors: Carvajal Horacio G , Wan Fei , Brar Anoop K , Liu Chang , Eghtesady Pirooz
Published: November 2020

Introduction:
Congenital heart disease (CHD) arises from many etiologies, ranging from genetic to environmental exposures, such as viral infections. The human leukocyte antigens (HLA) play an important role in the immune response to pathogens. HLA has been extensively explored and linked with several diseases; no such investigations, however, have been done in context of CHD.

Hypothesis:
We sought to identify potential HLA associations with CHD in a large population sample with molecular-based HLA typing.

Methods:
Available data on race, gender, HLA-A, B, and DRB1 typing (1-field, antigen level) was collected from the 2,349 patients in the United Network for Organ Sharing (UNOS) database undergoing heart transplant due to CHD between 2005 and 2017. These were compared to all 80,893 deceased kidney donors in the same period. Nominal variables were compared with Pearson’s chi-square, and logistic regression was used to compare all HLA antigens between groups, adjusting for race and gender. The false discovery rate was used to control for multiple comparisons, with adjusted p-values <0.05 considered significant.

Results:
There were 14 HLA-A, 25 HLA-B, and 14 HLA-DRB1 antigens with an overall frequency of 1% or higher. The frequency of HLA-A*30, B*44, and DRB1*08 differed significantly between groups (Table 1). Unconditional regression showed significantly increased odds of CHD in patients with HLA-A*30 and HLA-DRB1*08, as well as significantly lower odds in those with HLA-B*44 (Table 1). The demographics between groups were comparable, with the exception of fewer Caucasians in the cases (CHD 60.7% vs controls 65.6%, p=0.026). When adjusted for race and gender, only HLA-A*30 remained statistically significant.

Conclusions:
HLA-A*30 appears to be linked with CHD independent of race. Further analyses with detailed CHD diagnoses and high-resolution HLA typing data are needed to explore potential associations between specific cardiac defects and HLA at the allele level.
Abstract 13646: Clinical Profile and Ablation Outcomes in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy and Biventricular Involvement
Authors: Shen Lishui , Zheng Lihui , Yao Yan
Published: November 2020

Background:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive disease which can involve both ventricles. This study aimed to elucidate the clinical profile and ablation efficacy in Chinese ARVC patients with biventricular (BiV) involvement.

Methods and Results:
Based on cardiovascular magnetic resonance findings, 255 ARVC patients were divided into two groups: the BiV involved group (n=137) and the isolated right ventricular (RV) involved group (n=118). Patients with BiV involvement were more likely to suffer from heart failure (28.5% vs. 8.5%;
P
<0.001) and recurrent syncope (32.8% vs. 21.2%;
P
=0.038), and presented with lower heart transplantation-free survival and composed endpoint (death or heart transplantation)-free survival (all
P
<0.05). Of the 255 subjects, 52 BiV involved patients and 77 isolated RV involved patients underwent catheter ablation for ventricular tachycardia (VT). After 5 years’ follow-up, the outcomes including VT recurrence and all-cause mortality in 2 groups showed no difference (all
P
>0.05). The age, amount of induced VT during electrophysiology study and non-acute procedural success (partial success, defined as inducing the same VT with cycle length 30% longer after ablation; substrate modification only) were independent predictors of VT recurrence in BiV involved patients (all
P
<0.05).

Conclusion:
BiV involvement in ARVC indicated worse symptoms and poor prognosis. Nonetheless, catheter ablation remained effective for VT control in this population. The younger age, more induced VTs and non-acute procedural success were associated with VT recurrence after ablation.
Abstract 13654: Air Pollution, Environmental Greenness, and Total Cardiovascular Disease Mortality
Authors: Aitken William W , Wang Kefeng , Parrish Abraham , Celli Diego , Lombard Joanna , Szapocznik Jose , BROWN Scott C
Published: November 2020

Introduction:
Air quality is a major environmental determinant of health. Environmental greenness – a measure of vegetative presence – has been associated with reduced risk of cardiovascular disease. However, the impact of greenness on the relationship between air pollution and cardiovascular disease (CVD) has been less studied.

Hypothesis:
Environmental greenness is associated with reduced total CVD mortality and mediates some of the relationship between air pollution and CVD mortality.

Methods:
The Centers for Disease Control and Prevention Interactive Atlas of Heart Disease provided national CVD death rates, Environmental Protection Agency air quality measurements (particulate matter PM2.5), and Census sociodemographic information (age, race, education, and income) by county across the United States. These data were matched to mean county normalized difference vegetation index (NDVI) derived from National Aeronautics and Space Administration (NASA) Moderate Resolution Imaging Spectroradiometer (MODIS) 250 m spatial resolution data. Linear regression modeling estimated the relationship between air pollution and greenness on CVD mortality using SAS version 9.4 software. Mediation analysis of greenness on the relationship between air pollution and CVD mortality was then conducted.

Results:
Ambient concentration of PM2.5 ranged from 3 to 19.7 μg/m3 with a mean of 9 μg/m3 ± 1.9 μg/m3 and NDVI ranged from 0.00 to 0.80 with mean of 0.41 ± 0.13. For every 0.1-unit increase in NDVI, CVD mortality decreased by 13.2 deaths per 100,000 adults (p = 0.0001). For every 1 μg/m3 increase in PM2.5, CVD mortality increased by 38.8 deaths per 100,000 adults (p < 0.0001). Mediation analysis suggests that NDVI is a statistically significant mediator of the PM2.5 to CVD mortality relationship, with NDVI explaining 4.3% of this relationship (p=0.0009).

Conclusions:
Our analysis of air quality, environmental greenness, and CVD death rates demonstrates that greenness is independently associated with reduced CVD morality and also mediates the relationship between air pollution and CVD mortality. The evidence suggests that environmental interventions to increase greenness and reduce air pollution may reduce excess cardiovascular mortality.
Abstract 13655: Chronic Kidney Disease Progression and Prediction of Clinical Cardiovascular Disease and Total Mortality: The Coronary Artery Risk Development in Young Adults (cardia) Study
Authors: Duprez Daniel A , Choi Yuni , Shroff Gautam R , Chu Haitao , Kramer Holly J , Jacobs David R
Published: November 2020

Introduction:
The Kidney Disease Improving Global Outcomes (KDIGO)Guidelines proposed a chronic kidney disease (CKD) risk assessment matrix based on estimated glomerular filtration (eGFR) together with albuminuria categories (urine albumin-to-creatinine (ACR)). This classification system tends to focus on nuances at the severe CKD end of the spectrum among middle-aged and older adults. We expanded the KDIGO risk categories to include less severe manifestations of CKD, applicable to a generally healthy population in young adulthood.

Hypothesis:
CKD progression in its less severe range is common and predicts CVD and total mortality starting in generally healthy young adults.

Methods:
In a community-based sample of black and white men and women, both eGFR (creatinine) and spot urine ACR were assayed at study year 10 (age 27-41y) and every 5 y for 20 y through year 30. We expanded the 4 KDIGO risk categories by adding 2 less severe categories (see Figure). We estimated CKD stage prevalence at each exam and transition probabilities, including 4389 participants by year 30. We used proportional hazards regression with time-varying CKD stage, age, sex, and race as predictors of the endpoints any incident CVD or total death.

Results:
As expected, extreme risk was seen in 131 people (3% prevalence) who reached stages 4-6 (See Figure). Important increases in risk (hazard ratios 1.55 to 3.11) occurred in 1601 people (36% prevalence) who reached stages 2-3. Transition to higher stage (mostly by 1 stage) occurred in 5-10% per 5 years (~30% in 20 years).

Conclusions:
These data suggest that clinically important changes occur in CKD risk staging throughout middle age, though most of these changes are currently regarded as minor occurrences. Research should explore whether more aggressive, low risk treatment options, which currently exist, would be beneficial in people with small changes in CKD stage, starting in young adulthood.
Abstract 13667: Programming to S1PR1
+
Endothelial Cell Population Promotes the Restoration of Vascular Integrity
in vivo
Authors: Akhter Zahid , Joshi Jagdish Chandra , Balaji Ragunathrao Vijay Avin , Proia Richard L , Malik Asrar B , Mehta Dolly
Published: November 2020

Introduction:
Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate the endothelial cell (EC) regenerative programs facilitating thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1).

Hypothesis:
We postulate that S1PR1
+
EC serve as an endogenous means to prevent endothelial injury.

Methods:
Studies were made using EC-S1PR1 null mice and S1PR1-GFP reporter mice to trace the generation and characteristics of S1PR1
+
EC by exploiting immuno-histochemical analysis and FACS. RNA-seq analysis was performed to identify the genetic signature of S1PR1
+
EC. Combination of genetic and pharmacological strategies were included for mechanistic study. Transplantation of S1PR1
+
EC and edema measurement was performed in EC-S1PR1 null mice.

Results:
We observed in a mouse model of endotoxemia that LPS via generation of S1P induced the programming of S1PR1
lo
EC to S1PR1
+
EC, comprising 80% of lung EC. Their generation preceded the vascular repair phase and these cells were required for reestablishing the endothelial barrier function. Thus, conditional deletion of S1PR1 in EC spontaneously increased lung vascular permeability. RNA-seq analysis of S1PR1
+
EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively, as well as transcription factors EGR1 and STAT3. EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively to increase S1P concentration that served to amplify S1PR1
+
EC transition. Transplantation of S1PR1
+
EC into injured lung vasculature of EC-S1PR1
-/-
mice restored endothelial integrity.

Conclusions:
Findings illustrate that generation of a specialized S1PR1
+
EC population has the potential to activate key endothelial regenerative program mediating vascular endothelial repair raising the possibility of activating this pathway to restore vascular homeostasis in inflammatory lung injury.
Abstract 13675: Impact of Antithrombotic Therapy on Clinical Outcomes in Patients With Type B Acute Aortic Syndrome
Authors: Masumoto Akiko , Kaji Shuichiro , Miyoshi Yutaro , Pak Misun , Okada Taiji , Toyota Toshiaki , Sasaki Yasuhiro , Kim Kitae , Kitai Takeshi , Kobori Atsushi , Ehara Natsuhiko , Kinoshita Makoto , Furukawa Yutaka
Published: November 2020

Introduction:
In type B acute aortic syndrome (B-AAS), degree of false lumen thrombosis is known to affect clinical outcome. Antithrombotic therapy might have impact on prognosis through affecting false lumen thrombosis.We aimed to assess the impact of antithrombotic therapy on clinical outcomes in patients with B-AAS.

Methods:
A total of 429 patients with acute B-AAS admitted to our hospital and discharged alive were retrospectively analyzed. The primary outcome was aorta-related adverse events, defined as a composite of aorta-related death, aortic rupture, surgical or endovascular aortic repair and progressive aortic dilation.

Results:
Of the 429 patients, 72 patients (17 %) were discharged with antithrombotic therapy and 357 (83 %) without antithrombotic therapy. 254 patients (59 %) presented with intramural hematoma with complete thrombosis of false lumen, and 175 (41 %) presented with classic aortic dissection. Reasons for prescription were coronary artery disease (n=25), cerebral ischemia (n=17) and others (n=30). In the antithrombotic group, patients were significantly older than no-antithrombotic group (73 ± 13 vs 67 ± 13 years, P= 0.001) and had more comorbidities such as dyslipidemia (40 % vs 26 %, P= 0.011), diabetes mellitus (22 % vs 11 %, P= 0.007) and coronary artery disease (36 % vs 5 %, P< 0.001). During a mean follow-up of 4.8 ± 5.2 years, 37 patients (51 %) in the antithrombotic group and 98 patients (27 %) in the no-antithrombotic group had a primary outcome event. Event-free survival rate among antithrombotic versus no-antithrombotic group was 36 % vs 73 % at 5 years (P< 0.001). Multivariate Cox regression analysis adjusted for age, sex, comorbidity and medication revealed that antithrombotic therapy was a significant risk factor for aorta-related adverse events (hazard ratio 2.08, 95% confidence interval 1.247-3.463; P= 0.005).

Conclusion:
In B-AAS, antithrombotic therapy was associated with an increased risk of aorta-related events. For patients with indispensable need of antithrombotic therapy, careful follow-up should be provided.
Abstract 13692: Cardiorespiratory Fitness and Atrial Fibrillation Risk in African American Veterans
Authors: Tsimploulis Apostolos , faselis charles , Rashba Eric J , Moore Hans , Karasik Pamela , Kokkinos Peter F
Published: November 2020

Introduction:
Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting >10 million in the USA. The beneficial effects of cardiorespiratory fitness (CRF) on cardiovascular (CV) diseases are well-documented. Interestingly, African American (AA) individuals are less prone to develop AF. Little is known about the association between CRF and AF in AA men.

Hypothesis:
CRF-AF risk association in AA men.

Methods:
We identified 11,216 AA Veterans with a mean age (±SD) 58±11 years who completed a symptom-limited exercise treadmill test at the VAMCs in Washington DC and Palo Alto CA. None exhibited evidence of ischemia or AF during and prior to it. We established four fitness groups based on age-specific quartiles of peak metabolic equivalents (METs) achieved: Least-Fit: 4.4 ±1.2 METs (n=2,530); Moderate-Fit: 6.6±1.3 METs (n=3,361); Fit: 8.1±1.4 METs (n=2,719) and High-Fit: 11.2±2.4 METs (n=2,606). AF was identified by a search of the medical records CPRS (database) using ICD coding and verified by 2 investigators. Cox proportional hazard models adjusted for age, CV disease, CV medications and risk factors were constructed to assess the CRF-AF association. P-values <0.05 using two sided tests were considered statistically significant.

Results:
During a mean follow-up period of 10.7±6.2 years, 1,423 patients developed AF; 421(16.6%) in the Least-Fit, 366 (10.9%) in Moderate-Fit, 323 (11.9%) in Fit and 313 (12%) in the High-Fit group. The CRF-AF association was inverse and graded. When compared to the patients in the Least-Fit group, the AF risk in the Moderate-Fit group was 29% lower (HR=0.71; 95% CI: 0.62-0.82, p<0.001). For Fit and High-Fit patients, the risk was 37% (HR=0.63; 95% CI: 0.54-0.73, p<0.001) and 51.0% lower (HR=0.49; 95% CI: 0.42-0.57, p<0.001), respectively.

Conclusion:
In this cohort, higher fitness levels reduced and delayed the risk of atrial fibrillation. The CRF-AF association was inverse, graded and independent of comorbidities.
Abstract 13699: Cyclohexanone Contamination of Medical Plastics is Associated With Worse Congenital Heart Surgery Outcomes
Authors: Park Christin Y , Kuiper Jordan , Buckley Jessie , Ellis Greg , Graham David , Graham Eric M , Everett Allen D
Published: November 2020

Introduction:
Cyclohexanone, an industrial medical plastic fabrication contaminant, can leach from medical plastics including the cardiopulmonary bypass (CPB) circuit. Effects of neonatal perioperative cyclohexanone exposure on hospital-based outcomes have not been explored.

Hypothesis:
We hypothesize that serum cyclohexanone during congenital heart surgery with CPB is associated with worse morbidity.

Methods:
The study was a secondary analysis of 107 neonates enrolled in the NHLBI-funded Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial. Blood samples were collected preoperatively, post-CPB, and 12 hours postoperatively, and concentrations of cyclohexanone and its metabolites were quantified using mass spectrometry. Using the geometric mean of cyclohexanone concentrations, the effects of an interquartile range (IQR) increase in concentration on hospital-based outcomes was assessed using adjusted linear and Poisson regression, for continuous and dichotomous outcomes, respectively. Estimates were reported as % differences (linear regression) or relative risks (Poisson regression) with 95% confidence intervals.

Results:
In adjusted analyses, an IQR increase in mean cyclohexanone concentration was associated with greater time spent on mechanical ventilation (40.1%: 7.34%, 82.9%), in the ICU (20.1%: 1.36%, 42.2%), and in the hospital (20.8%: 3.28%, 41.3%), and less time spent alive and out of the hospital 90 days post-surgery (-17%: -30.9%, -0.36%). An IQR increase in mean cyclohexanone was associated with a 61% (RR: 1.61; 1.19, 2.17) greater risk of the trial primary morbidity-mortality composite outcome (death, cardiac arrest, ECMO, renal or hepatic insufficiencies, and lactic acidosis). An IQR increase in mean cyclohexanone metabolites was associated with a 29% (RR: 1.29; 1.07, 1.55) greater risk of developing low cardiac output syndrome.

Conclusions:
This study showed that in neonates, circulating cyclohexanone was associated with unfavorable hospital-based outcomes following cardiac surgery with CPB, suggesting that medical plastic contamination may contribute to morbidity. Therefore, reducing exposure to cyclohexanone perioperatively may improve congenital heart surgery outcomes.
Abstract 13701: Change in Caregiver Burden From Before to 1 Year After Surgery: Findings From the Sustaining Quality of Life of the Aged: Transplant or Mechanical Support (
Sustain-IT
) Study
Authors: Okwuosa Ike , Andrei Adin-cristian , Liu Menghan , PETTY Michael G , Hsich Eileen M , Dew Mary Amanda , sciortino christopher , Pham Duc T , Yancy Clyde W , Warzecha Anna , HARTUPEE Justin , Cotts William , Pamboukian Salpy , Pagani Francis D , Lampert Brent , Johnson Maryl R , Murray Margaret , Takeda Koji , yuzefpolskaya melana , Silvestry Scott C , Spertus John A , Kirklin James K , Collum Craig , Grady Kathleen L
Published: November 2020

Purpose:
Caregivers (CGs) for patients with advanced heart failure (HF) assist in HF-specific disease management. In the SUSTAIN-IT study, we reported CG perception of difficulty and time needed to perform tasks for patients awaiting surgery in 3 groups: HF patients awaiting heart transplant (HT) without mechanical support (HT-non-MCS), HF patients awaiting HT bridged with mechanical support (HT-MCS), and HF patient awaiting left ventricular device implantation as destination therapy (DT-MCS). In this report, we compare CG perceived burden from baseline to 1 year after surgery.

Methods:
We enrolled 301 CGs of HF patients between 10/1/15-12/31/18 from 12 U.S. hospitals: 193 awaiting HT (92 with and 101 without MCS), and 108 scheduled for DT-MCS. Prior to surgery and 3, 6, and 12 months after surgery, CGs completed the Oberst Caregiver Burden Scale (OCBS) which has 15 items with 2 subscales: (1) time and (2) difficulty: range=1-5, higher score=more time required for tasks and more task difficulty. Analyses included t-tests, chi-square tests, and baseline-adjusted linear regression models.

Results:
CGs were age 61.0±10.3 years, the majority were spouses (85%), female (86%), and white (86%). Average time spent on caregiving was moderate and decreased significantly from baseline to 12 months after surgery for all groups (Figure). DT-MCS CGs spent significantly more time than HT CGs on tasks 12 months after surgery. There were no significant differences in perceived difficulty (which was low) in performing CG tasks in all groups from baseline to 12 months. DT-MCS CGs did perceive tasks to be more difficult than HT CGs at 12 months.

Conclusion:
CGs of advanced HF patients adapted well to assisting with care, without increased burden, 1 year after HT and DT-MCS surgery. CGs of DT-MCS patients required more time and reported CG tasks to be more difficult than HT CGs. Understanding differences in CG burden will aid in pre surgical risk discussions and post-surgical follow-up.