bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 21057: Combined Administration of DNMT and HDAC6 Inhibitors Suppress Endotoxemia Induced Macrophages Pro-Inflammatory Signaling Pathway
Authors: Zhou Zhigang , Samanta Saheli , Rajasingh Sheeja , Barani Bahar , Drosos Nicholas , Wang Rui-Lan , Dawn Buddhadeb , Rajasingh Johnson
Published: March 2022

Background:
Acute lung injury (ALI) is an common inflammatory disease that affects millions of people worldwide. Therapies based on a new understanding of disease pathogenesis are needed. Studies have shown that treatment with a single drug is not effective in controlling the pro-inflammatory response caused by ALI.

Hypothesis:
The combinatorial epigenetic treatment with 5-Aza-2’-deoxycytidine (Aza, a DNMT inhibitor) and Tubastatin-A (TBSA, a HDAC6 inhibitor) after LPS-induced ALI would mitigates the pro-inflammatory P38-MAPK signaling and rescues animal from ALI-induced death.

Methods:
Acute lung injury was induced in C57BL mice by intraperitoneal injection of LPS (10mg/kg). One hour later, the mice received either vehicle, Aza (1mg/kg), TBSA (0.25mg/kg), or Aza+TBSA. After 12 hours, the mice were sacrificed for further biochemical and histological analyses. To delineate the signaling mechanism, we have used macrophage cell line (RAW 264.7). For this, macrophages were treated with vehicle, LPS (1ug/ml), Aza (50nM), TBSA (750nM), or with combined treatment for 30 min and 24 hours for Western and qRT-PCR analyses.

Results:
We observed that all mice treated with LPS and LPS+Aza died within 24 hrs. The mice treated with LPS+TBSA exhibited 20% survival rate whereas the LPS+Aza+TBSA- treated group displayed 80% survival rate. Our results revealed that LPS significantly increases the expression of inflammatory cytokines such as iNOS, IL-6 and TNF-α in macrophages. However, the increased mRNA expression was significantly reduced after treatment with Aza+TBSA
(Fig. A)
. We also found that Aza+TBSA suppressed the LPS-induced P38-MAPK signaling pathway
(Fig. B)
.

Conclusion:
We report for the first time that Aza+TBSA together reverses the outcome of ALI induced by endotoxemia.
Abstract 21066: Cardiac Specific Knockdown of
Hsl
, a Candidate Gene From Human Studies at High Altitude, Improves Hypoxia Tolerance in
Drosophila
Authors: Babakhanlou Madlina , Stobdan Tsering , Haddad Gabriel G
Published: March 2022

Rationale:
Human adaptation to high altitude hypoxia can potentially enlighten us for better therapeutic modalities for sea level diseases that involve hypoxia and ischemia in their pathogenesis. Using whole genome sequencing, we identified
LIPE
(Lipase E, Hormone Sensitive Type), as a candidate gene involved in HA adaptation. This gene is highly conserved and the ortholog in
Drosophila
i.e.,
Hsl
, when globally knocked down and tested for hypoxia tolerance, significantly improves survival rates in low oxygen.

Objective:
To understand the hypoxia tolerance mechanism in
Hsl-
knockdown
Drosophila
.

Methods and Results:
We knocked down
Hsl
in individual tissue-types by crossing tissue specific
Gal4
drivers with UAS-
RNAi(Hsl)
lines. To elucidate its potential role in hypoxia tolerance, we measured the eclosion rate (%) at 5% O
2
and compared with controls kept at room air (21% O
2
). Remarkably, the eclosion rate for
Hsl
, at 5% O
2
, when knocked down specifically in heart (UAS-
RNAi(Hsl)
X
Hand-Gal4
) was significantly higher (86.02%; P<0.05) when compared to the background controls (42.2% for
w1118
, 50.06% for
Hand-Gal4
and 39.72% for UAS-
RNAi(Hsl)
).

Conclusion:
These data indicate that a lower level of
Hsl
in the heart significantly improves hypoxia tolerance in
Drosophila
. Interestingly, also during cardiac-ischemic-hypoxia, the cardiomyocytes strategically knockdown
LIPE
, preventing lipid metabolism and therefore reduce oxygen consumption when the supply is limited.
Abstract 21091: Heterotypic Interaction of Endothelial and Adipose Mesenchymal Stem/Stromal Cells Induces Activin A Expression Through Juxtacrine Notch Signaling Pathways
Authors: Merfeld-Clauss Stephanie , Lu Hongyan , Jones Thomas J , Feng Dongni , March Keith L , Traktuev Dmitry O
Published: March 2022

The interaction between human endothelial (EC) and adipose mesenchymal stem/stromal cells (ASC) leads to EC reorganization into stable vascular structures
in vitro
and functional vessels
in vivo
and ASC maturation from progenitor to smooth muscle/pericyte phenotype. We have previously shown that juxtacrine EC-ASC interactions induce in ASC to express activin A, which, by affecting both EC and ASC bioactivities, plays a central role in vasculogenesis. Here, a co-culture model of human cord blood-derived EC and human ASC was used to study the role of Notch2 and Notch3 in juxtacrine mechanism-mediated regulation of activin A expression in ASC. Blockade of Notch signaling by the γ-secretase inhibitor DAPT, between days 1-3 following heterocellular contact, prevented induction of activin A secretion, and DAPT added to co-cultures after establishment of activin A secretion almost completely abrogated its production, suggesting the need for uninterrupted Notch signaling to enforce continued activin A production. In parallel, DAPT reduced ASC differentiation towards the mural phenotype, and increased EC proliferation, causing inefficient vasculogenesis. Silencing Notch2 expression in ASC prevented activin A production by ASC when in co-culture with EC, whereas silencing Notch3 expression amplified its secretion. Dual silencing experiments revealed that silencing Notch2 was dominant, eliminating the effect of silencing Notch3. In parallel, Notch2 was not involved in mediating differentiation of ASC towards a smooth muscle/pericyte fate, whereas silencing of Notch3 led to an increase in baseline expression of markers of smooth muscle phenotype, which was further enhanced on contact with EC. Overall, Notch3 inhibits both expression of activin A and smooth muscle/pericyte differentiation program. Furthermore, these data suggest that activin A is induced exclusively through
trans
signaling mechanisms, whereas mural differentiation program is also regulated through
cis
pathways.
Abstract 21097: Three-Dimensional Traction Stresses Facilitate Leukocyte Diapedesis
Authors: Yeh Yi-Ting , Ricardo Serrano , François Joshua , Chiu Jeng-Jiann , del Álamo Juan Carlos , Chien Shu , Lasheras Juan Carlos
Published: March 2022

Objective:
Leukocyte extravasation is critical in the immune response. Leukocytes transmigrate from apical to basal endothelium preferentially through VEC junctions three-dimensionally (3D), a process known as diapedesis. However, the precise biomechanical mechanisms by which the leukocyte-VEC interaction contributes to diapedesis remain elusive.

Method:
We conducted time-lapse imaging experiments to monitor the dynamics of VEC junctions during leukocyte diapedesis. We used 3D Traction Force Microscopy (3DTFM) and Monolayer Stress Microscopy to measure the spatiotemporal evolution of the traction stresses and intracellular tensions generated by the cells and to characterize the sequence of mechanical events during leukocyte diapedesis. We acquired 4-6 experiments for the statistical analysis.

Results:
We found that leukocyte firm adhesion caused the opening of junctional gaps before the initiation of leukocyte transmigration. We measured significant changes of in-plane stress and intracellular tension while the leukocyte firmly attached to VECs, and subsequently, the following increases of out-of-plane stress as the leukocyte migrates across the monolayer. Thrombin treatment increased the heterogeneity of VEC monolayer tensions, which created a VEC environment that facilitated leukocyte diapedesis. Subsequent treatment with Rho kinase inhibitor reversed the thrombin effect.

Conclusion:
The coordination between 3D traction stresses and VEC monolayer tensions, controls the dynamics of leukocyte diapedesis.
Abstract 21103: Annual Trends Outcomes and Disparities of Hemodynamic Support Utilization for Ventricular Tachycardia Ablation in Congestive Heart Failure Population in United States
Authors: Vuddanda Venkat , Jazayeri Mohammad-Ali , Turagam Mohit K. , Shah Zubair , Balla Sudarshan , Settipalle Bhanu Harshita , Avula Sindhu Reddy , Sheldon Seth H , Yeruva Madhu Reddy , Lakkireddy Dhanunjaya R.
Published: March 2022

Introduction:
There is limited real world data evaluating the role of hemodynamic support (HS) during ventricular tachycardia (VT) ablation in congestive heart failure (CHF) patients.

Hypothesis:
We sought to investigate the annual trends, gender and racial disparities in utilization of HS and hospital mortality after VT ablation with HS in CHF population.

Methods:
Using the U.S. National Inpatient Sample (NIS) database from 2010-2014, we identified all discharge records with CHF (CCS code 108) and a primary diagnosis of VT (ICD-9-CM diagnosis code 427.1) undergoing catheter ablation (ICD-9-CM procedure code 37.34). Records with diagnosis of supraventricular arrhythmia and cardiogenic shock were excluded. Patients receiving HS on the day of VT ablation were identified using respective ICD-9-CM procedure codes, percutaneous ventricular assist device [pVAD] 37.68, and extracorporeal membrane oxygenation [ECMO] 39.65. Statistical analyses were performed using R (Vienna, Austria). To account for the single cluster stratified random sampling design of NIS, R survey package was used to obtain national estimates. Proportions were compared with Chi-Square test, and p trend computed using Mann-Kendall test.

Results:
Of 6,837 VT ablations, 353 (5.1%) were performed with HS. Use of HS consistently increased over the study period (0.37% vs. 3.64%; p trend <0.001). Age adjusted hospital mortality was higher in patients receiving HS (4.2% vs. 2.0%; p < 0.001). Men and minority races (blacks, hispanics) had higher use of HS. Among patients who received HS, women and minority races had higher age adjusted hospital mortality
(Figure)
.

Conclusion:
Utilization of HS for VT ablation is increasing in this nationally representative population. Unadjusted rates show disparities in the use of HS, with lower use in women and caucasians. Hospital mortality was higher in patients receiving HS, with disproportionately high rates in women and minorities.
Abstract 21106: The Matrikine Proline-Glycine-Proline is Locally Generated Following Acute Arterial Vascular Injury
Authors: Payne Gregory A , Xing Dongqi , Viera Liliana , Li Jindong , Xu Xin , Jackson Patricia , Blalock J. Edwin , Gaggar Amit
Published: March 2022

Introduction:
Neointimal formation following vascular injury remains a clinically significant obstacle. Endovascular procedures, including percutaneous coronary intervention, disrupt the endothelium leading to inflammation and cellular proliferation within the vessel wall. Extracellular matrix (ECM) degradation by matrix metalloproteases (MMPs) has increasingly been understood to generate bioactive chemokines (i.e. matrikines) capable of causing cellular activation. Despite this knowledge, the contribution of matrikine signaling to vascular injury remains poorly understood.

Hypothesis:
We examined the hypothesis that the pro-inflammatory matrikines Proline-Glycine-Proline (PGP) and acetylated-PGP (AcPGP) are generated following acute arterial vascular injury.

Methods:
20 male, c57bl/6 mice underwent unilateral carotid ligation of the left common carotid artery. Suture was passed, but not tied, under the contralateral carotid artery to serve as a sham procedure. Mice were sacrificed at Days 0, 1, 3 and 14 (n = 5 mice per day). Carotids and serum were harvested and processed for biochemical analysis. PGP and AcPGP were measured using liquid chromatography-tandem mass spectrometry, while total and pro-MMP9 was measured by ELISA.

Results:
Sham arteries had no significant induction of total or pro-MMP9 at any time. In contrast, ligated arteries showed a robust induction of both total and pro-MMP9 by Day 1 that was sustained through Day 14 (P < 0.0001 compared to mean sham arteries at all days). Importantly, PGP concentrations from ligated arteries showed a significant and sustained increase compared to Sham arteries by Day 3 (mean 150 vs 20 pg/mg carotid, P < 0.0001), while no difference was observed in AcPGP concentrations. Serum PGP and AcPGP concentrations remained low and unchanged throughout the 14-day experiment (mean ~100 and 20 pg/mL respectively).

Conclusions:
The current results identify PGP as a novel matrikine associated with acute vascular injury. AcPGP has previously been shown to activate endothelial cells to increase permeability and endothelin-1 synthesis via CXC Chemokine Receptor 2 (CXCR2). These results implicate PGP, a similar CXCR2 ligand, as a potentially novel mediator of inflammation following vascular injury.
Abstract 21108: Early Evidence That the Female Genome Does Matter for Acute Coronary Syndrome Risk
Authors: Dungan Jennifer R , Qin Xuejun , Singh Abanish , Kraus William E , Hauser Elizabeth
Published: March 2022

Introduction:
Women of all ethnicities have the highest rates of Acute Coronary Syndrome (ACS) misdiagnosis, delayed treatment, and ACS-related near-term mortality. Known physiologic differences and traditional risk factors have failed to fully explain these ACS disparities among women. Our knowledge gap of genomic variation underlying women’s unique ACS phenotypes means that there is no female-derived ACS risk biomarker that reflects female-specific biology and phenotype features. Among 510 women, we previously identified 122 SNPs within 14 genomic regions that significantly predicted ‘survivorship in CAD’ (all-cause mortality among coronary artery disease cases; p<10-5); none of which were significant in males or controls. Given the recent recognition of sex as a biological variable, our purpose was to identify female-specific genomic markers that predict ACS case status.

Methods:
We performed secondary case-control analysis for 1,382 females (796 ACS cases/586 non-ACS controls) of the Duke Catheterization Genetics (CATHGEN) Study (Illumina Human Infinium 1.0 platform). ACS was defined as having no previous MI history plus either documented unstable angina pain type or incident myocardial infarction. We employed logistic regression models of ACS case status for each SNP separately, assuming additive genetic models, and controlling for age and 3 PCAs of ethnicity.

Results:
Twenty-three SNPs among 3 biologically relevant candidates (
LPAGT1
,
SLC9A9
, &
RAP1GAP2
) significantly predicted women’s ACS (range p=7.43x10
-5
- 0.05) with positive and negative odds ratios observed.
LPGAT1
is involved in cardiolipin synthesis;
SLC9A9
is involved in endosome recycling; and,
RAP1GAP2
regulates secretion of dense granules from platelets at endothelial damage sites. Additionally, 74 SNPs within the 11 novel survivorship with CAD candidates significantly predicted ACS (p<0.05).

Conclusions:
We demonstrate proof of principal for
unique
, female-specific genomic effects on ACS case status; and, shared genomic variation with ACS and survivorship in CAD among women. Validation of this work is required. Future research is needed to identify female-derived genomic markers that may uniquely characterize women’s ACS and coronary disease expression.
Abstract 21122: Contribution of
ABCA1
Genetic Variation to Plasma Lipid Levels in Non-Hispanic White Americans
Authors: Niemsiri Vipavee , Wang Xingbin , Radwan Zaheda H , Pirim Dilek , Halder Indrani , Reis Steven E , Hokanson John E , Hamman Richard F , Barmada M M , Feingold Eleanor , Demirci F Y , Kamboh M I
Published: March 2022

Introduction:
Dyslipidemia [i.e., elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG); decreased level of high-density lipoprotein cholesterol (HDL-C)] is one of the risk factors for cardiovascular disease (CVD). Genetics play an important role in inter-individual variation of lipid levels. ATP-binding cassette A1 (ABCA1), a membrane transporter, mediates cellular phospholipid and cholesterol efflux. Mutations in
ABCA1
gene cause Tangier’s disease (OMIM #205400) presented with HDL-C deficiency, as well as, increased risk for developing CVD. In this study, we aimed to identify both common [minor allele frequency (MAF)≥5%] and uncommon (MAF<5%) variants of
ABCA1
associated with inter-individual variation in major lipid traits.

Methods:
We resequenced 50 exons and exon-intron boundaries of
ABCA1
in a selected set of 95 individuals with extreme HDL-C levels (≤10
th
and ≥90
th
%tile), and subsequently genotyped selected variants in the entire sample of 623 US Non-Hispanic Whites. With resequencing, we identified 404 variants, and for genotyping we selected 250 variants (216 from sequencing data, 34 from HapMap-CEU data). A total of 182 successfully genotyped and QC-passed bi-allelic variants were tested for association with plasma lipid levels.

Results:
Gene-based test showed evidence of association between
ABCA1
and TG (
p
=0.0108). Single-site association analyses demonstrated 26 common variants nominally associated (
p
<0.05) with at least one lipid trait. After multiple testing correction, two variants [rs4743763 with TC levels,
p
=0.0005; rs2066716 (Thr1427Thr) with TG levels,
p
=0.0016] remained significant. Furthermore, rs2066716 (Thr1427Thr) was among 11 out of 26 lipid-associated
ABCA1
variants for which the replication data were available in an independent sample (
n
=744) and it remained significantly associated with TG levels in the meta-analysis (meta-
p
=0.0088). Rare variant analyses revealed association of multiple sets of rare variants with lipid traits.

Conclusions:
Our findings support the genetic contribution of
ABCA1
, both common and rare variants, to lipid levels in humans.
Abstract 21126: Association Between Household Income and Intake of Aspirin for Prevention of Coronary Artery Disease: Insights From the BRFSS 2015 Database
Authors: Maan Abhishek , Baturin Brian , Arunachalam Karuppiah , Gjelsvik Annie , Shah Nishant
Published: March 2022

Introduction:
The current USPSTF guidelines recommend use of aspirin for primary prevention of CAD in adults aged between 50-69 years. In our study, we sought to determine the association of household income and socioeconomic factors and the use of aspirin for the primary prevention of CAD in the eligible population.

Methods:
After excluding the participants with prior diagnosis of CAD, those who had a condition which would make the use of aspirin unsafe and missing data on household income, we analyzed a total of 3,913 participants from the Behavioral Risk Factor Surveillance System 2015 database for our study. We performed univariate comparison of various covariates in two categories of participants based on an income threshold of 50,000$. Subsequently, we performed logistic regression and stepwise modeling approach for multivariable analyses to assess the association between the use of aspirin (outcome) and various covariates.

Results:
In an unadjusted logistic regression model, the participants with household income < $15,000 were 67% less likely to use aspirin (OR: 0.33, 95% CI: 0.23-0.47, p< 0.0001) in comparison with the reference group of > $50,000 household income. After adjusting for race, education, insurance, gender, household size and cholesterol awareness in our fully adjusted model, we observed that the participants with household income of $35,000 to $50,000 were 53% less likely to take aspirin for prevention of CAD as compared to referent group of income > 50,000$ (adjusted OR: 0.47, 95% CI: 0.28-0.76, p = 0.003). The participants of Hispanic race were also about 43% less likely to take aspirin as compared to Caucasians (adjusted OR: 0.57, 95% CI: 0.40-0.80, p = 0.002).

Conclusions:
Our findings highlight significant disparities in the use of aspirin for primary prevention of CAD potentially reflecting the role of income and racial factors. A targeted approach to address the use of aspirin in these subgroups might be beneficial.
Abstract 21133: Platelet Vesicle-Engineered Stem Cells for Enhanced Delivery to Heart Injury: Rodent and Porcine Studies
Authors: Tang Junnan , Zhang Jinying , Cheng Ke
Published: March 2022

Introduction:
Stem cell transplantation is currently implemented clinically, but is limited by low retention and insufficient targeting to the injured heart. Platelets have the natural ability to home to injury and play an important in recruiting stem cells to the sites of injury on blood vessels.

Hypothesis:
We seek to harness the natural injury-homing ability of platelets to enhance the vascular delivery of cardiac stem cells (CSCs) to myocardial infarction (MI) injury.

Methods:
We fuse platelet nanovesicles (PNVs) onto the surface of CSCs to form engineered PNV-CSCs. This strategy is nontoxic to CSCs. The ability of PNV-CSCs for binding onto the injured vessel is tested
ex vivo
. Rat and pig models of ischemia/reperfusion are established to test PNV-CSCs.

Results:
PNV-CSCs possessed surface markers of platelets, which are associated with platelet adhesion to injury sites. PNV-CSCs can selectively bind collagen-coated surface and denuded rat aorta
ex vivo
. In rats and pigs with ischemia/reperfusion injury, PNV decoration increases CSC retention in the heart and augments therapeutic benefits. PNV-CSCs treatment robustly boosts cardiac function with the highest left ventricular ejection fraction and best cardiac morphology by promoting angiomyogenesis.

Conclusions:
The engineered PNV-CSCs possess the natural targeting and repairing ability of their parental cells: platelets and of CSCs. This method offers fast, straightforward, and safe manipulation of stem cells with no genetic alterations of the cells and is generalizable to multiple cell types.
Abstract 21150: Surgical Treatment of Asymptomatic Severe Aortic Stenosis: Impact of Surgical Timing on Long-Term Survival
Authors: Kim Ho Jin , Kim Joon Bum , Jung Sung-Ho , Choo Suk Jung , Chung Cheol Hyun , Lee Jae Won
Published: March 2022

Introduction:
Aortic valve (AV) replacement (AVR) is regarded as the only effective treatment for severe aortic stenosis (AS). The current guidelines, however, agree with watchful waiting in asymptomatic AS patients with normal left ventricular (LV) function.

Hypothesis:
This study aims to assess the hypothesis that timely surgical intervention is associated with the improved long-term survival in asymptomatic severe AS patients.

Methods:
Between 2000 and 2015 in our institution, we identified 505 patients (aged 63.9±13.1 years, 252 females) having asymptomatic severe AS (aortic valve area [AVA] ≤ 1.0cm
2
, peak trans-AV velocity [V
max
] ≥ 4.0m/s or mean AV pressure gradient [PG] ≥ 40mmHg) with preserved LV function (ejection fraction ≥ 50%). Among them, very severe AS (AVA ≤ 0.6cm
2
, V
max
≥ 5.0m/s or mean PG ≥ 60mmHg) was found in 152 (29.9%) patients. AVR was performed in 231 (45.7%) patients within 3 months after diagnosis (n=145) or during follow-up (n=86) thereafter either by surgical AVR (n=214) or by trans-catheter AVR (n=17). Time-varying Cox-proportional hazard models were used to determine the impact of surgical therapy on survival outcomes.

Results:
During a median follow-up of 58.3 months (Q1-Q3, 29.6-104.6 months), 163 (32.3%) patients died. On time-varying Cox-hazard models, surgical therapy was associated with a significant risk reduction in overall death (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.43-0.94; P=0.022) after adjusting with 32 significant risk factors for mortality. Survival benefits by AVR were consistently demonstrated in most risk subgroups of patients based on ages, severity of AS and the morphology of the AV (bicuspid) (Figure).

Conclusions:
Timely AVR in asymptomatic severe AS patients resulted in marked survival benefits. These study results may suggest that early robust recruitment for surgical therapy may be warranted in asymptomatic severe AS patients before developing ventricular deterioration or onset of symptoms.
Abstract 21153: The Atrial Fibrillation Ethnic Paradox: Insights From National Inpatient Sample Database
Authors: Kowlgi N. Gurukripa , Gunda Sampath , Padala Santosh , Ellenbogen Kenneth A
Published: March 2022

Introduction:
It has been reported that African-American (AA) patients have lower incidence of atrial fibrillation (AF) as compared to their Caucasian (C) counterparts. However, precise differences in incidence of the traditional risk factors in the above groups have not been described in large population cohorts.

Hypothesis:
To confirm and further delineate previously reported ethnic trends in AF patients amongst AA and C.

Methods:
We retrospectively analyzed 8,080,123 hospitalized patients between the years 2011-2013 from the National Inpatient Sample database. All patients with a principal diagnosis of AF based on ICD-9-CM code of 427.31 (n = 932,303, 11.5%) formed the study cohort and were further sub-categorized into C and AA cohorts. Chi-square and one-sample T test were used to compare the traditional risk factors between AA and C patients with AF.

Results:
AF incidence in C was 12.9% vs 5.5% in AA (p < 0.001). AA were younger (69.57 ± 28.49 years vs. 76.81 ± 23.2 years, p < 0.05 ) and had less men (46.6% vs. 49.9%). AAs had higher prevalence of hypertension (75.9% vs. 70%), congestive heart failure (26.5% vs. 23.3%), diabetes mellitus with (8.4% vs 5.3%) or without complications (33% vs. 25.2%), renal failure (35.5% vs. 22.2%), obesity (16.6% vs. 11.8%), smoking (8.4% vs 6%) and alcohol consumption (3.9% vs. 2.7%). C however had a higher prevalence of coronary atherosclerosis (41.7% vs 35.9%). All of the above were statistically significant with a p-value < 0.001 with 95% confidence intervals.

Conclusion:
Our data demonstrates a significant AF ethnicity paradox. Despite higher prevalence of traditional risk factors for AF, AA had >2-fold lower incidence of AF compared to Cs. Possible hypothesis for the above includes under-diagnosis of AF in AA, age differences, or yet unknown pathophysiological features of AF. While the former can be addressed with vigilant clinical practice, the latter would need further research.
Abstract 21164: New Pulmonary Vein Derived Theory of Atrial Fibrillation
Authors: Qin Mu , Liu Xu
Published: March 2022

Introduction:
Pulmonary veins (PV) is a major source of triggers for AF. However, the mechanism underlying the rapid firing of PV muscle sleeve is not fully understood.

Hypothesis:
AF is related to the compensatory increase in PV load in patients with pneumonectomy.

Methods:
A cohort of 128 patients were recruited and assigned to three groups, group 1: patients with left-sided pneumonectomy (N = 47), group 2: patients with right sided pneumonectomy (N = 21), and control group: patients with paroxysmal AF (N = 60). All patients underwent echocardiography and CT scan preoperatively; PVI was performed in three groups; 24-hour Holter monitoring was performed during 1-year of follow-up.

Results:
All patients in group 1 and 2 had paroxysmal AF, occurring decades after pneumonectomy. No inter-group differences in left atrial diameter were seen. The average diameter of LSPV (17.2±1.4 mm) and LIPV (14.7±1.2 mm) in group 1 was larger than those in control group (13.6±1.0 mm and 9.9±0.9 mm, P<0.01). The diameter of RSPV and RIPV in group 2 (15.1±1.3 mm and 14.5±1.1 mm) and control group (13.2±1.3 mm and 10.2±1.2 mm) also showed significant differences (P<0.01). Electrical activity in group 1 and 2 could be recorded in all the PV stumps. After isolation of contralateral PV, AF was terminated in 91.5% and 85.7% of patients in group 1 and group 2. During follow-up, the incidence of AF episodes was not significantly different among three groups.

Conclusions:
the PV-derived mechanism of AF depends on a compensative increase in contralateral PV load in patients that have undergone pneumonectomy, and partial PV mediated AF is hard to progress into persistent state.
Abstract 21167: Impact of Sex-Mismatch on Heart Transplantation: A Meta-Analysis and Systematic Review
Authors: Blumer Vanessa , Arcay Luis , Khalafi Mehdi , Mendirichaga Rodrigo , Zablah Gerardo , Hernandez Gabriel A , Macon Conrad , Chaparro Sandra
Published: March 2022

Introduction:
Limited research has explored heart transplantation (HT) outcomes in patients with sex-mismatched organ donors and recipients. Findings on which type of sex-mismatch has worse post-transplant outcomes have been contradictory.

Methods:
We searched Medline, Embase, Scopus and Cochrane for publications reporting HT outcomes according to donor/recipient sex mismatch through May 2017. Sex mismatched HT male recipients were compared to non-mismatched male recipients, and sex mismatched HT female recipients were compared to non-mismatched female recipients. Outcomes were compared under the random-effects model and heterogeneity examined via Chi
2
and I
2
statistics. Sensitivity analyses were performed.

Results:
A total of 8 studies including 110211 patients were included in the analysis. Of these, 80% were male recipients and 29% had sex-mismatched transplants. In male recipients, sex mismatch was associated with a higher rate of rejection (OR 1.25; 95% CI 1.19-1.32; p<0.00001). In female recipients, sex mismatch was associated with less rejection (OR 0.72; 95% CI 0.53-0.97; p=0.03). Sex mismatch was not associated with early mortality in either sex. Mortality at 10 years had a tendency of being greater in both male and female mismatched patients; however, the heterogeneity was high and it did not achieve statistical significance (Figure 1).

Conclusions:
Our analysis suggests that sex-mismatch in HT may affect the incidence of rejection without necessarily having clear impact on mortality. Sex-mismatch in HT remains an area in need of investigation and further studies are needed to determine if sex-mismatch truly influences HT outcomes.
Abstract 21168: Heart Failure With Preserved Ejection Fraction (HFpEF) Outcomes After Same Hospital Readmission versus Different Hospital Readmission
Authors: Patel Nilay V , Arora ShilpKumar , Sabhrawal Sera , Kumar Varun , Tripathi Byomesh , Aneja Ekta , Sharma Kriti , Dave Mihir , Patel Neil , Setarah Sam , Kondoor Vishwa , Mishra Abhishek , Bhatia Subir , Bharadwaj Bhaskar , Patel Smit , Malik Priti , Gidwani Umesh , Gopalan Radha
Published: March 2022

Introduction:
Heart failure with preserved ejection fraction(HFpEF) is a syndromemwith limited treatment modalities. Our control over 30 day readmissions and readmission outcomes is limited.

Methods:
HCUP’s Nationwide Readmissions Database (NRD) from 2013-14 was used for HFpEF related hospitalizations using ICD-9- CM diagnostic code:428.3x in primary diagnosis field. 30-day readmissions were identified and classified into two groups: same-hospital readmissions and different-hospital readmissions. A comparative analysis was conducted focused on three metrics - mortality, length of stay (LOS) and cost of hospitalization. We used hierarchical two-level modeling and propensity score matching to adjust for confounders.

Results:
Of the 94,988 readmitted patients (age >65 years: 79%, Females: 61.45%) - 76,665 (80.70%) to the same hospital and rest to different hospitals. After adjusting extensive list of confounders, same hospital readmission was associated with better outcomes including in hospital mortality (OR: 0.73, 95% CI: 0.66 - 0.80, p<0.001), LOS (Days: -1.14, 95% CI: -1.31 - -0.97, p<0.001), Cost of care ($: -4208, 95% CI: - 4681 - -3734, p<0.001). For validation of our results, we ran propensity score matching, showed similar results - in hospital mortality (6.23% vs 8.07%), LOS (6.30 ± 0.08 vs 7.47 ± 0.095), Cost of care (14042.7 ± 215.7 vs 18685.4 ± 279.2). Post hoc high-risk subgroup analysis were conducted and showed similar results (Figure). Number needed to treat (for mortality) was 74 patients. Up to ~ 100 million dollars could have been saved over 2 years.

Conclusions:
Considering scale of problem and limited option to prevent worse outcomes, Simple interventions such as redirecting patient to same hospital as previous admission would be beneficial.
Abstract 21171: Combinatorial Aso-Mediated Knockdown of ApoB and DGAT2 Inhibits Both VLDL Secretion and High Fat Diet Induced Hepatic Steatosis
Authors: Fedotova Tatyana , Hernandez-Ono Antonio , Gibeley Sarah , Ginsberg Henry
Published: March 2022

We previously demonstrated that mice fed a Western-type and treated with apoB antisense (ASO) for 6 weeks had both reductions in VLDL secretion and the same levels of hepatic triglycerides (TG) as did mice receiving control ASO. The reduction in hepatic TG was due to trapping of TG that had been transferred to the ER lumen by MTP where it was trapped because of the knockdown (KD) of apoB. Trapped ER-TG stimulated endoplasmic reticulum (ER) autophagy (A), which transported ER-TG to lysosomes where it was hydrolyzed to fatty acids (FA) that were oxidized by mitochondria. We have used this model in test if ASO treatment to KD apoB together with either diacylglycerol-acylt-transferase-1 (DGAT1) or DGAT2 ASO-KD would (1) reduce hepatic TG to levels below mice receiving only control ASO, and (2) provide insights into whether either DGAT1 or DGAT2 preferentially transferred newly synthesized TG into the ER. ASO-KD of either DGAT1 or DGAT2 alone reduced secretion of apoB and TG about 30-40%, but hepatic TG was much greater than controls with DGAT1 KD and less than controls with DGAT2 KD. Combined KD of either apoB and DGAT1 or apoB and DGAT2 inhibited apoB and TG secretion similarly by about 70-80%, the same degree of inhibition as with apoB ASO alone. Both double KD approaches reduced hepatic TG to below that of either control or apoB ASO alone, but hepatic TG with combined apoB-DGAT2 KD was about half of that seen with apoB-DGAT1 KD: combined apoB-DGAT2 KD had hepatic TG that was reduced by 75% versus control ASO-treated mice and similar to levels we see with chow diets. As we previously reported, apoB KD for 6 weeks caused ER autophagy and increased FA oxidation; levels of ER autophagy and FA oxidation with combined apoB-DGAT1 KD were similar to apoB KD alone. Importantly, combined apoB-DGAT2 KD had both more ER autophagy and greater increases in FA oxidation than either apoB KD or apoB-DGAT1 KD. Thus, apoB-DGAT2 KD could be a promising therapy for reduction of apoB-lipoproteins without hepatic steatosis. The results also indicate that TG synthesized by DGAT1 is preferentially transferred to the ER compared to DGAT2 generated TG.
Abstract 21187: A Novel Mutations in
DPP10
Linked to Inherited J Wave Associated With Sudden Infant Death Syndrome by Augmentation of K
v
4.3 Channel Current
Authors: Barajas Hector , Pfeiffer Ryan , Powers Andy , Carrier Tabhita , Wu Yuesheng , Knilans Timothy , Hu Dan
Published: March 2022

Introduction:
Mutations in genes encoding the α (
KCND3)
and β (
KCNE3
) subunits of genes encoding the cardiac transient outward potassium (Ito) have been associated with inherited cardiac arrhythmia syndromes such as Brugada Syndrome (BrS) and Sudden Infant Death Syndromes (SIDS).

Hypothesis:
Novel genetic variant in
DPP10
associated with severe pediatric J Wave Syndrome (JWS), IVF and SIDS.

Methods:
The proband, a 16 year-old female, presented with atrial fibrillation and atrial septal defect. Subsequently she developed accentuated J waves in all ECG leads leading to repeated episodes of VT/VF (Type 3 ERS). Cilostazol proved effective in quieting VT/VF. She died of an electrical storm at 21 years of old. Genetic screening using Next Gen and Sanger methods uncovered a genetic variant in
DPP10
but no variants in any other JWS susceptibility genes.

Results:
Transversion of thymine for guanine at nucleotide 15 predicted substitution of aspartic acid (D) for glutamine acid (E) at position 5 in exon 1b in the N-terminal of
DPP10 (E5D)
. The variation E5D was present in 5 unrelated patients with ERS (2), IVF (1) and BrS (3). E5D is highly conserved among species. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques at 37°C. Co-expression of
KCND3
+
KChIP2
+
DPP10
/E5D generated Kv4.3 current density (I
to
) 169.9% and 70.6% greater compared with
KCND3
+
KChIP2
+
DPP10
/WT when homozygously and heterozygously expressed, respectively (n=9-12, p<0.01). Inactivation of Ito and recovery from inactivation was slower in E5D channels. Quinidine (5 μM) and cilostazol (5 μM) inhibited I
to
by approximately 50% at +20 mV in E5D channels but less so (20 %) in WT channels.

Conclusions:
Our results provide, for the first time, evidence in support for the hypothesis that
DDP10
is a novel susceptibility gene for life threatening arrhythmias associated with JWS. Our data suggest that
DPP10-
E5D contributes to the generation of a pathogenic substrate by boosting Ito and that Quinidine and Cilostazol serve as therapeutic options in this setting by reducing I
to
.
Abstract 21206: Manf, a Structurally Unique Redox-Sensitive Chaperone, Restores ER-Protein Folding in the Ischemic Heart
Authors: Arrieta Adrian , Blackwood Erik A , Stauffer Winston T , Santo Domingo Michelle , Thuerauf Donna J , Doroudgar Shirin , Glembotski Christopher C
Published: March 2022

Rationale:
In cardiomyocytes, most secreted and membrane proteins are synthesized and folded in the sarcoplasmic/endoplasmic reticulum (SR/ER). We previously showed that during myocardial ischemia, decreased oxygen creates a reducing environment in the SR/ER, preventing protein disulfide isomerases (PDIs) from forming disulfide bonds in nascent proteins, causing ER stress, i.e. the toxic accumulation of unfolded proteins which contributes to cardiomyocyte death. In response to ER stress, the transcription factor, ATF6 induces chaperones that restore SR/ER protein folding. We found that ATF6 also induces mesencephalic astrocyte-derived neurotrophic factor (MANF), a recently identified protein of unknown function. MANF is structurally unique, so its function cannot be inferred from other proteins. Since MANF is induced by ATF6, is ER-localized, and possesses a conserved pattern of cysteines found in all known species of MANF, we hypothesized that MANF is a redox-regulated chaperone that optimizes cardiomyocyte viability during ischemia.

Methods:
The ability of MANF to bind misfolded proteins during reductive ER stress or ischemia were assessed in neonatal rat ventricular myocytes (NRVM). The ability of recombinant MANF (rMANF) to suppress aggregation of misfolded proteins was examined in an
in vitro
chaperone assay. Finally, the effects of MANF loss-of-function in the ischemic heart,
in vivo
, were determined by generating a transgenic mouse model that expresses a cardiomyocyte-specific MANF-targeted microRNA.

Results:
In NRVM subjected to reductive ER stress or simulated ischemia, MANF formed disulfide-linked complexes with misfolded proteins. Under reducing conditions, rMANF suppressed aggregation of model misfolded proteins
in vitro
, and mutant rMANF in which the cysteine residues were mutated to alanine did not suppress misfolded protein aggregation. MANF knockdown in the heart,
in vivo
, increased damage from myocardial infarction, and an AAV9-based gene therapy approach rescued the effects of MANF deficiency,
in vivo
.

Conclusions:
MANF is a redox-sensitive SR/ER-resident chaperone that is a critical contributor to SR/ER protein folding during the adaptive ER stress response and decreases tissue damage in the ischemic heart.
Abstract 21207: Use of Digoxin, an Inhibitor of Hypoxia Inducible Factor 1A Synthesis, is Associated With Decreased Incidence of Gastrointestinal and Arteriovenous Malformations Related Bleeding in Patients With Continuous-Flow Left Ventricular Assist Device
Authors: Vukelic Sasha , Vlismas Peter , Watts Sade , Saeed Omar , Sims Daniel , Patel Snehal R , Jorde Ulrich
Published: March 2022

Introduction:
Gastrointestinal bleeding (GIB) occurs in 20-40% of patients with continuous flow left ventricular assist device (CF-LVAD) during the first years of follow up and is most commonly due to arteriovenous malformations (AVM). Although the precise pathophysiology of AVM formation during CF-LVAD support has not been established, it is postulated that hypoperfusion in the splanchnic vascular territory and resultant hypoxia may activate the angiogenesis signaling cascade
via
the HIF1α/angiopoietin-2 pathway. Interestingly, digoxin is a potent inhibitor of HIF1α synthesis.

Hypothesis:
We hypothesize that digoxin therapy can be associated with a decrease incidence of GI and AVM bleeding in CF-LVADs patients.

Methods:
Charts of all adult patients implanted with CF-LVAD between February 2006 and February 2017 were reviewed with emphasis on occurrence and etiology of GIB. Kaplan Meier (KM) and logistic regression analysis were used to assess the frequency of overall GI and AVM bleeding and their association with digoxin therapy.

Results:
Sixty-two of 204 patients (30%) experienced a GIB and 20 of 62 (32%) bleeds were due to AVM. Both overall frequency of GIB (18% vs 37% of patients, p < 0.05) and AVM bleeding (3% vs 14% of patients, p < 0.05) were lower in the 73 patients receiving digoxin compared to the 131 patients not receiving digoxin during an average observation time of 516 and 446 days, respectively. Survival free of GIB was significantly higher in digoxin treated patients in KM analysis (Fig1). Multivariate logistic regression analysis revealed that digoxin therapy was independently associated with a reduced risk for overall GIB (odds ratio 0.35, 95% confidence interval 0.17-0.75) as well as AVM bleeding (odds ratio 0.19, 95% confidence interval 0.35-0.52).

Conclusions:
Use of digoxin was associated with a significant reduction in overall GIB as well as AVM bleeding. Prospective studies are needed to validate this finding and its mechanistic underpinnings.
Abstract 21209: Prevalence and Clinical Outcome of Thrombus Detected on Transvenous Leads at the Time of Lead Extraction
Authors: Ho Gordon , Mehta Ishan , Maus Timothy T , Khoche Swapnil , Hsu Jonathan C , Pollema Travis L , Birgersdotter-Green Ulrika , Pretorius Gert V
Published: March 2022

Introduction:
The prevalence and clinical significance of incidental thrombus formation on transvenous leads is not well characterized. We performed a prospective cohort study of patients referred for transvenous lead extraction to evaluate the prevalence and short term major clinical outcomes of thrombus detected on transvenous leads.

Hypothesis:
Thrombus incidentally detected on transvenous leads is not associated with major adverse clinical outcomes.

Methods:
Consecutive patients referred for transvenous lead extraction for non-infectious indications such as lead malfunction were enrolled. Routine pre-operative trans-esophageal echocardiograms were performed prospectively for all patients, focusing on all transvenous leads from the superior vena cava to endocardial insertion points to examine for thrombus. Clinical endpoints of mortality and cardiovascular morbidity (symptomatic pulmonary embolism, myocardial infarction or cerebrovascular accident) were assessed at minimum 1 month follow-up clinic visit or phone call.

Results:
Out of 166 patients referred for lead extraction, 111 patients had non-infectious indications and were included in the analysis. Lead thrombi were detected in 22 patients (20%). Baseline characteristics including age (65±13 vs 61±16 yrs, p=0.9) and age of implanted leads (99±68 vs 88±57 months, p=0.5) were similar between patients with and without lead thrombi. There were no deaths, myocardial infarction, pulmonary embolism, nor stroke in patients with thrombi. Median length of follow up was 9 months.

Conclusions:
Incidental thrombi on transvenous leads are commonly found in patients referred for transvenous lead extraction and are rarely associated with short-term major adverse outcomes. Careful extraction of leads with small incidentally detected thrombi can be performed without major clinical sequelae. Larger studies are needed to further assess the long term clinical significance of lead thrombi.
Abstract 21215: A Multi-Institutional Study on Pediatric Heart Transplant Outcomes: Does a Positive Blood Culture Donor Matter?
Authors: Amdani Shahnawaz M , Du Wei , Aggarwal Sanjeev
Published: March 2022

Introduction:
Active infection at time of organ procurement for heart transplantation may increase recipient morbidity and mortality.

Hypothesis:
Recipients of blood culture positive donors (BCPD) will have higher rates of early and late morbidity and mortality.

Methods:
A retrospective review of the Organ Procurement and Transplant Network data on pediatric patients (≤18 years) undergoing heart transplantation between 1987-2015 was conducted. BCPD and non-BCPD were identified. Baseline donor and recipient characteristics was compared using t-test or Mann-Whitney U test and chi-square test as appropriate. Kaplan-Meier curves were generated for patient survival.

Results:
Of 9,618 heart transplant recipients, 450 (4.7%) were from BCPD. BCPD were more often African American (23.8 vs. 18.9 %, p 0.001); had tattoos (7.8 vs. 5.3%, p 0.03); needed inotropic support (41.3 vs. 26.7, p <0.0001) and died of drug intoxication (3.6 vs. 1.2%, p <0.0001). Recipients of BCPD were more often Hispanic (18.8 vs. 14.7, p =0.014); had a diagnosis of congenital heart disease (19.1 vs. 13.7, p=0.003) or restrictive cardiomyopathy (6.4 vs. 4.3, p=0.003); longer duration of Status 1A listing (34.6 ± 56.8 vs. 24.9 ± 56.1 day, p=0.0003); more likely treated for blood stream infections within two weeks prior to transplant (25.3 vs. 16.3%, p <0.0001); required inotropic support (46.2 vs. 38.3, p= 0.0007); ECMO (6.9 vs. 4.8, p= 0.04); inhaled Nitric Oxide (1.3 vs. 0.5%, p= 0.01) or ventricular assist device (75.6 vs. 58.5%, p <0.0001). Proportion of BCPD increased after 2009 (7.7 vs. 1.5%, p <0.0001). Outcomes between both groups were no different [time to extubation (31.9 ± 171 vs. 21.1 ± 134 hours, p= 0.72); hospital length of stay (27.2 ± 29.3 vs. 27.7 ± 31.9 days, p=0.77); need for dialysis (7 vs. 6.7%, p=0.79); stroke (3.2 vs. 2.8%, p= 0.66);incidence of rejection episodes in the first year (28.7 vs. 33.8%, p=0.07)]. There were no differences in median (IQR) patient survival [17.7(11.5-not estimable) vs. 13.3(12.6 -14.1) years, p= 0.15].

Conclusions:
Transplantation utilizing BCPD has increased over time. Recipients of BCPD appear to be at high risk for waitlist mortality. Despite this, morbidity and mortality was not higher for such recipients.