bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15826: SCUBE1 Controls BMPR2-relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension
Authors: Sun Wei , Tang Ying , Tai Yi-Yin , Handen Adam , Zhao Jingsi , Speyer Gil , Al Aaraj Yassmin , Watson Annie , Romanelli Makenna , Sembrat John C , Rojas Mauricio , Simon Marc A , Zhang Yingze , Lee Janet S , Xiong Zeyu , Dutta Partha , Vasamsetti Sathish , McNamara Dennis M , McVerry Bryan , MCTIERNAN Charles F , Sciurba Frank , Kim Seungchan , Smith Akaya , Mazurek Jeremy A , Han Yuchi , Vaidya Anjali , Nouraie Mehdi , Kelly Neil , Chan Stephen Y
Published: November 2020

Introduction:
Pulmonary arterial hypertension (PAH) is a morbid vascular disease where mutations of bone morphogenetic protein receptor 2 (BMPR2) control pulmonary endothelial pathophenotypes. Transcriptomic screening from endothelial cells (ECs) derived from hereditary BMPR2-driven disease offers an opportunity to identify novel effectors in PAH pathogenesis.

Methods:
Public RNA-sequencing data were analyzed from inducible pluripotent stem (iPS) cell-derived endothelial cells with and without BMPR2 mutations. Candidate genes were assessed in cultured pulmonary arterial ECs (PAECs) and in rodent and human PAH. Correlations were assessed of human plasma expression with clinical disease indices.

Results:
Signal Peptide CUB-EGF-Domain Containing Protein 1 (SCUBE1), a putative binding partner to BMPR2, was differentially expressed in ECs carrying BMPR2 mutations. SCUBE1 was enriched in PAECs, dependent on hypoxia inducible factor-1α, and downregulated by PAH triggers, including BMPR2 knockdown, hypoxia, and IL-1β exposure.
In vitro
analyses defined SCUBE1 as a pathogenic effector activating BMPR2-associated SMAD1/5/9, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with pulmonary hypertension due to left heart disease, or in the patients of other acute and chronic cardiopulmonary pathologies, including pneumonia, acute lung injury, chronic obstructive pulmonary disease, ischemic heart disease, and cardiomyopathy. An optimal plasma SCUBE1 cut point of 5.02 ng/mL was defined to diagnose PAH from control cohort with a sensitivity of 0.65 and a specificity of 0.82. In PAH patients, plasma SCUBE1 levels negatively correlated with pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular dysfunction.

Conclusions:
Guided by iPSC-EC sequencing, SCUBE1 was identified as a downregulated secreted factor in PAH, controlling endothelial pathophenotypes and correlated with disease indices. Clinically, SCUBE1 is a sensitive and specific PAH diagnostic marker. It may also serve as a therapeutic target given its inherent links to controlling PAH predisposition and severity.
Abstract 15832: Endothelial Shear Stress Assessment in Coronary Arteries: Comparison Between 3d Reconstructions Based on Invasive and Noninvasive Imaging
Authors: Eslami Parastou , Hartman Eline , Karady Julia , Thondapu Vikas , Albaghdadi Mazen , Jin Zexi , Cefalo Nicholas , Lu Michael T , STONE Peter H , Wentzel Jolanda J , Hoffmann Udo
Published: November 2020

Introduction:
Endothelial shear stress (ESS) identifies coronary plaques at high risk for progression and rupture leading to a future acute coronary syndrome. We developed an optimized methodology to derive ESS using computational fluid dynamics (CFD) in 3D models of coronaries from noninvasive computed tomography angiography (CTA). We
hypothesized
that ESS based on CTA has a high correlation with ESS based on the gold standard fusion of intravascular ultrasound (IVUS)/optimical coherence tomography (OCT) and CTA.

Methods:
In 14 patients, paired patient-specific CFD models based on invasive and CTA imaging of the left anterior descending (LAD) coronaries were created. 10 were used to optimize, and 4 patients to test the methodology. Time averaged ESS (TAESS) was calculated for both coronary models applying physiological data at the time of imaging. Each 3D reconstructed coronary was divided into 2 mm segments and further subdivided into 8 arcs (45
o
). TAESS was averaged per segment and arc. The paired segment and arc averaged TAESS were categorized into patient-specific tertiles (low, medium and high).

Results:
In the 10 LADs, used for optimization of the methodology, we found high correlations between invasively- and noninvasively-derived TAESS averaged over segments (n=263, r=0.86) and arcs (n=2104,r= 0.85,p<0.001). The correlation was also strong in the 4 test patients with r=0.95 (n=117 segments p=0.001) and r=0.93 (n=936 arcs p=0.001). There was a high concordance of 78% of the three TAESS categories comparing both imaging at the segments and 76% at the arcs in the first 10 patients. This concordance was lower in the 4 test patients (64% and 64% in segment and arc averaged TAESS).

Conclusions:
We showed that we can accurately assess the TAESS distribution noninvasively from CTA and demonstrated a high correlation with TAESS using IVUS/OCT 3D models. Future studies should prove the prognostic value of CTA-based TAESS for plaque progression and clinical events.
Abstract 15839: Patients With Abdominal Aortic Aneurysms Have Reduced Levels of MicroRNA 122-5p in Circulating Exosomes
Authors: Lopez Jose L , Ramirez Joel L , Anh Phu Tuan , Duong Phat , Bouchareychas Laura , Kuhrau Christina R , Lin Pei Yu , Conte Michael S , Vartanian Shant M , Raffai Robert L , Oskowitz Adam Z
Published: November 2020

Introduction:
There are currently no specific biomarkers to screen and monitor disease progression in abdominal aortic aneurysms (AAA), which are the 15
th
leading cause of death in the United States. Circulating exosomes contain microRNAs (miRNA) that are potential biomarkers of disease. This study aimed to characterize the exosomal miRNA expression profile of patients with AAA in order to identify novel markers of disease.

Methods:
A total of 109 patients scheduled to undergo a duplex ultrasound (US) for screening or surveillance of AAA were screened to participate in the study. Eleven patients with AAA (max aortic diameter >3cm) and 15 non-aneurysmal controls (max aortic diameter <3cm on screening US) were enrolled. Circulating plasma exosomes were isolated using Cushioned-Density Gradient Ultracentrifugation and total RNA was extracted. Next Generation Sequencing was performed on the Illumina HiSeq4000 SE50 after NEBNext Multiplex Small RNA Library Prep. Differential miRNA expression analysis was performed using DESeq2 software with a Benjamini-Hochberg correction. MicroRNA expression profiles were validated by Quantitative Real-Time PCR.

Results:
Aortic diameter, as measured by US, was significantly larger in the AAA group (mean maximum diameter 5.2 vs 2.3 cm,
p
=2.84x10
-6
). Aneurysm patients were more likely to suffer from CAD (5/11 vs 1/15,
p
= 0.05) but had similar levels of PAD (4/11 vs 2/15,
p
=0.35) and COPD (4/11 vs 4/15,
p
=0.68) compared to controls. A total of 40 miRNAs were differentially expressed (
p
<0.05). Of these, 18 miRNAs were up-regulated and 22 were down-regulated in controls compared to AAA. After false discovery rate (FDR) adjustment, only miR-122-5p was expressed at significantly different levels in AAA compared to controls (fold change = 5.03 controls vs AAA; raw
p
= 1.8x10
-5
; FDR
p
=0.02).

Conclusions:
Plasma exosomes from AAA patients have significantly reduced levels of miRNA-122-5p compared to controls.
Abstract 15845: Heart Heroes: A Gamified Mhealth Platform to Measure Continuous Cardiac Health Data in the Outpatient Setting of Adolescent Patients With Known and Suspected Heart Disease
Authors: Miller Jennifer C , Barrett Trevor , Patel Neil , Souza Andrew , Wood John , Saxon Leslie A
Published: November 2020

Introduction:
Adolescents with heart disease report difficulty in communication about their health as a major inhibiting factor in their care. MHealth technologies collect health data in daily life and enable health data sharing between the provider and patient. The adolescent population has a high level of engagement with mobile devices and a willingness to use them for health-related activities.

Hypothesis:
We hypothesized that our novel gamified mHealth platform Heart Hero can engage adolescent patients in the collection of cardiac health data in their daily life.

Methods:
We designed the research app using ResearchKit to collect continuous physiological data from the Apple Watch and daily survey data on well-being, stress, medical adherence, and cardiac symptoms. Patients were provided the app, iPhone, and Apple Watch and enrolled for 27 days. A final in-app survey was provided to assess feedback. We enrolled 28 patients total who were scheduled for outpatient cardiopulmonary exercise testing.

Results:
Mean age was 14.3 years old (SD +/-3.08) with a 1:1 M:F ratio. 61% of patients were ≥ 15 years of age. 94% of patients completed the final survey. Subjects on average completed 64% (SEM +/-5) of the daily quizzes with an average daily adherence of over 50% wearing the watch. 100% reported they liked using the watch and app, and 89% would like to continue wearing the Apple Watch. 53% reported the study encouraged them to exercise more while 21% reported encouragement to walk more. Fig 1 demonstrates A) Apple Watch and b) daily survey data collected from a patient throughout the study.

Conclusions:
In conclusion, Heart Hero is a mHealth platform which can successfully be used to collect continuous health data from the adolescent population with high engagement characterized by adherence and positive patient feedback. Adherence to the app was notably superior to the initial 5 ResearchKit applications enrolling adult patients.
Abstract 15864: Measured versus Estimated Resting Metabolic Rate in Heart Failure With Preserved Ejection Fraction
Authors: Anderson Theresa , Cascino Thomas , Perry Daniel , Grafton Gillian , Koelling Todd M , Hummel Scott L
Published: November 2020

Introduction:
Obesity is common in heart failure with preserved ejection fraction (HFpEF) and dietary weight loss can improve functional capacity, but sarcopenia and frailty are also frequently present. Little evidence is available regarding resting metabolic rate (RMR) or how commonly used equations to estimate RMR compare to measured RMR in HFpEF. This information is vital for counseling patients on individual caloric needs.

Hypothesis:
Commonly used estimation equations do not accurately reflect measured RMR in patients with HFpEF.

Methods:
Resting metabolic rate (RMR) was measured with a metabolic cart for consecutive patients with HFpEF (EF ≥50%) referred for right heart catheterization at the University of Michigan from 2011-2015. Patients with congenital, infiltrative, hypertrophic, or restrictive cardiomyopathy were excluded. The RMR was calculated using the Weir formula: RMR= 1440*[3.94 VO
2
(l/min) + 1.11*VCO
2
(l/min)] kcal/day. Measured RMR and estimations of RMR using the Harris Benedict Equation (HBE), Mifflin-St Jeor Equation (MSJE), and World Health Organization (WHO) equation were compared using paired t-tests and Bland-Altman plots.

Results:
Patients (n=43) were aged (mean ± SD) 62 ± 11.6 years, 53% female, and BMI 34.9 ± 11. Mean measured RMR from Weir equation was 1514 ± 479 kcal/day. Estimated RMR by HBE was 1784 ± 530, MSJE was 1685 ± 457, and WHO equation was 1816.8 ± 485 kcal/day. All estimations significantly overestimated RMR when compared to the Weir method (>10% difference and p<0.01 for all; Figure A-C). The MSJE had the closest range of agreement to the measured RMR.

Conclusions:
Estimations of resting metabolic rate in patients with HFpEF demonstrated a fixed bias towards overestimation when compared to measured RMR by metabolic cart. Given HFpEF populations are often obese and are counseled routinely on weight loss, understanding the implicit bias of equations estimating RMR is vital when providing nutritional and dietary counseling.
Abstract 15867: Flexibility Modifies the Age-related Arterial Stiffness in Women With Systemic Lupus Erythematosus
Authors: Hernandez Martinez Alba , Sola-Rodriguez Sergio , Vargas-Hitos Jose A , Gavilan-Carrera Blanca , Rosales-Castillo Antonio , Soriano-Maldonado Alberto
Published: November 2020

Introduction:
Systemic lupus erythematosus (SLE) is an autoimmune multisystemic disease associated with premature cardiovascular disease morbidity and mortality. Arterial stiffness is an age-dependent powerful cardiovascular risk predictor, which is elevated in SLE. The elasticity of the vascular wall and muscle flexibility are both partially determined by elastin-collagen composition, and whereas cardiorespiratory fitness seems to delay the age-related arterial stiffening in SLE, it might be speculated that flexibility (another component of physical fitness) could reduce the sympathetic nervous system dysfunction observed in patients with SLE and thus reduce arterial stiffness. However, whether higher flexibility is related to lower age-related arterial stiffness in SLE is unknown.

Hypothesis:
We assessed the hypothesis that flexibilitymay attenuate the negative effect of age on arterial stiffness in women with SLE.

Methods:
This cross-sectional study included 76 women with SLE (age 43.2, SD 13.8) with mild disease activity. Arterial stiffness was assessed with pulse wave velocity (PWV), flexibility by the back-scratch test, disease activity through SLEDAI, and cumulative organ damage with SDI, blood pressure by standardized methods and menopause status by questionnaire. Quantile regression tested the association of age, flexibility, and their interaction, with PWV (controlling for mean blood pressure, menopause, SLEDAI, SDI and corticosteroids exposure). Sample size was determined for a two-tailed test with a power of 0.8, significance
p
< 0.05 and effect size > 0.7 (n=34).

Results:
There was a back-scratchхage interaction effect on PWV (
p
<0.001). For women with -20 cm in the back-scratch test (i.e. short to touch her middle fingers behind the back), PWV was 0.107 m/s higher for 1-year increase in age, whereas for women with 15 cm, PVW was 0.064 m/s higher for 1-year increase in age.

Conclusion:
In conclusion, higher flexibility is associated with a lower increase in age-related arterial stiffness in SLE women. Further research is needed to determine whether improving flexibility through stretching exercises reduces the arterial stiffness associated with aging.
Abstract 15924: Identification of Gender- and Age-specific Top Predictors of Hospitalization Due to Heart Failure Using Machine Learning in TOPCAT
Authors: Dandi Gauri , Gani Nuha , Mallick Zyannah , Banerjee Avantika , Atkinson Ian , Xin Victoria , Qureshi Khizar , Lewis Natalie , Mahmood Nayab , Hasan Noah , Hayashi Scout , Haq Nowreen , Dey Amit , Husain Anwar , Rosenberg Yves D , Hasan Ahmed A
Published: November 2020

Background:
NHLBI supported Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) (NCT00094302) investigated whether treatment with spironolactone reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and a left ventricular ejection fraction over 45%. We reused publicly available individual patient-level data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses by machine learning (ML) on the American TOPCAT cohort (n=1767) to identify gender and age groups specific baseline (bl) predictors of hHF.

Methods:
The subjects were stratified into subgroups based on gender (male and female) and age (50-59, 60-69, 70-79, 80-90). Random Survival Forest (RSF), a non-parametric ML approach, evaluated 172 bl variables as predictors of hHF. Top 10 predictors were subsequently included in a multivariate Cox proportional hazards model.

Results:
The top 10 predictors of hHF are shown in Figure 1. Overall, renal and hematological biomarkers appeared prominently in the top 10 predictors for these patients. While liver markers were among top predictors for hHF in males, diabetes treatment and diabetic complications were top predictors for females. Also, diabetic treatment was a top predictor among age group 50-59, diabetic complications were top predictors among age groups 50-59 and 70-79, liver markers were top predictors among age groups 70-79, and race and years of smoking were top predictors among age group 60-69. Importantly, the use of potassium sparing diuretic at bl was the top predictor among age group 80-90.

Conclusion:
Using ML, we uncovered in an unbiased fashion, otherwise overlooked bl predictors of hHF in a large, international, multi-center trial like TOPCAT. Thus, ML can help to identify similarities and differences of disease and treatment outcomes among gender, race, ethnicity, and age specific subgroups and advance precision medicine.
Abstract 15945: Temporal Analyses of Chromatin Accessibility, Dna Methylation and Epigenomic Structure Identify Mechanisms of Locus-specific Regulation in the Heart
Authors: Rosa-garrido Manuel , Chapski Douglas J , Cabaj Maximilian , Morselli Marco , Ren Shuxun , Pellegrini Matteo , Wang Yibin , Vondriska Thomas M , Mason Rosibel J
Published: November 2020

Heart failure can be induced or ameliorated in animal models by regulation of chromatin modifying enzymes, yet the chromatin level actions of these enzymes during pathogenesis is unknown. Because many histone modifiers and transcription factors regulate gene expression, we sought to directly measure chromatin accessibility through an unbiased method (ATAC-seq) that reports the status of a given locus at any time—the sum total of all epigenetic modifiers—in a mouse model of pressure overload hypertrophy. Early compensation of pressure overload at 3 days was associated with widespread changes in chromatin accessibility and DNA methylation, primarily in noncoding regions. The majority of changes that persisted to the decompensated phase (3weeks) were already established at the earlier time point, revealing a temporal nature of epigenomic compensation to pathologic stimuli. A cardiac-specific CTCF depletion model was used to examine basal cardiac chromatin function and revealed that disruption of this structure by loss of CTCF causes widespread changes in accessibility and methylation distinct from those in pressure overload. Less than half of the gene expression changes occurring at either time point after pressure overload were explained by DNA methylation alone and accessibility was likewise an imperfect predictor of transcription. Distal enhancers were paired with genes based on chromatin structural data and the regulatory actions of these elements examined in the context of DNA methylation and accessibility: enhancer actions require specific combinations of transcription factors and histone modifications at different stages of disease and to execute aspecific transcriptional event (methylation or accessibility alone was insufficient to predict the behavior). For example, the subset of differentially accessible enhancers in both 3 weeks TACand CTCF depletion significantly overlaps with cardiac transcription factors Gata4 (p=4.13x10
-6
),Nkx2-5 (p=2.49x10
-5
) and P300 (p=8.38x10
-7
). In summary, these studies characterize the logic employed at coding, regulatory, and noncoding regions to regulate chromatin accessibility and transcription, providing a resource of epigenomic data at distinct temporal stages of heart failure.
Abstract 16253: Temporal Trends and Outcomes of Coronary Artery Bypass Grafting After Acute St-elevation Myocardial Infarction
Authors: Elbadawi Ayman , Elzeneini Mohammed , Elgendy Islam Y , Omer Mohamed , Ogunbayo Gbolahan O , Megaly Michael S , Jneid Hani
Published: November 2020

Introduction:
There is paucity of data on the outcomes of coronary artery bypass grafting (CABG) among patients presenting with ST-segment elevation myocardial infarction (STEMI).

Methods:
We queried the National Inpatient Sample database (2002-2016) for patients with STEMI who underwent CABG. We reported the trends in utilization of CABG for STEMI, and the associated in-hospital outcomes. Using multivariable analysis, we compared in-hospital outcomes in patients undergoing CABG on hospitalization day 1 vs. day 2 vs. day ≥3 , in the early (2002 to 2009) and contemporary cohorts (2012 to 2016).

Results:
Our analysis yielded 2,910,960 patients with STEMI, of whom 7.6% underwent CABG (9.6% in 2002 versus 3.9% in 2016, P
trend
<0.001). There was an increase in in-hospital mortality (5.8% in 2002 versus 7.6% in 2016, P
trend
<0.001) which corresponded to an increase in comorbidities burden among patients undergoing CABG. There was a rising trend in performing CABG on hospitalization day ≥ 3 corresponding to an increase in the utilization of MCS and pre-CABG PCI during the study years. CABG was more likely to be performed on admission day 1 in patients with anterior STEMI, cardiogenic shock or mechanical complications. In the early cohort, CABG on day 1 and day 2 was associated with higher in-hospital mortality, while in the contemporary cohort only CABG on day 1 was associated with higher in-hospital mortality compared with CABG on day ≥ 3. CABG on day 1 was associated with higher rate of cardiac arrest, hemorrhagic stroke, blood transfusion and cardiac tamponade in the earlier cohort, while in the more contemporary cohort it was associated with higher blood transfusion.

Conclusions:
There was a downtrend in performing CABG for STEMI, and an uptrend in in-hospital mortality after CABG. Patients undergoing emergent CABG on day 1 were more likely to have mechanical complications and cardiogenic shock and were associated with higher in-hospital mortality.
Abstract 16270: Genetic Susceptibility to Stress Associates With Higher Amygdalar Activity and Greater Myocardial Infarction Risk
Authors: Abohashem Shady , Osborne Michael , Choi Karmel W , Dar Tawseef , Ghoneem Ahmed , Abbasi Taimur , Zureigat Hadil , Naddaf Nicki , Liu Zhaowen , Smoller Jordan , Tawakol Ahmed A
Published: November 2020

Introduction and Hypothesis:
Chronic psychological stress is strongly linked to cardiovascular disease (CVD) risk. Metabolic activity of the amygdala, a stress-associated brain center, robustly associates with high inflammation and CVD risk. We hypothesized that a validated polygenic risk score for neuroticism (nPRS), a broad trait measure of vulnerability to stress, independently associates with 1) heightened amygdalar activity (AmygA) and 2) increased myocardial infarction (MI) risk

Methods:
Individuals (N=14349; median age (IQR): 64 (52, 74) yrs, 46%male) were identified from the Partners Biobank where genome wide nPRS and principle components of ancestry (PCI) were calculated. Using validated
18
FDG PET/CT imaging methods, AmygA was measured (N=995) as a target-to-background-ratio in individuals with clinical PET/CT imaging. MI was adjudicated using International Classification of Diseases (ICD) diagnoses. Traditional CVD risk factors
*
and psychiatric history were obtained using ICD codes and questionnaires. Independent t-tests and linear and logistic regression were employed

Results:
A total of 1708 (12%) individuals experienced MI. nPRS associated with AmygA (standardized β [95% CI]: 0.07 [0.01, 0.13], p=0.02
Fig A
) after adjustment for age, sex, and 10 PCI. It remained significant after additional adjustment for psychiatric history (p=0.02). AmygA also predicted MI in an adjusted model (OR: 1.50, p=0.006
*
). Importantly, after adjustment for age, sex, and 10 PCI, nPRS significantly associated with MI incidence (standardized OR [95% CI]: 1.12 [1.05, 1.17], p<0.001
Fig B
) and remained significant after additional adjustment for CVD factors (p=0.006*) and psychiatric history (p=0.007)

Conclusions:
These findings show for the first time that a genetic susceptibility to stress (high nPRS) associates with greater stress-related neurobiological activity, and MI risk. Further, these findings suggest nPRS may serve as a novel risk marker for MI
Abstract 16307: Tofogliflozin Improves Pulmonary Hypertension With Heart Failure With Preserved Ejection Fraction Mice
Authors: Joki Yusuke , Konishi Hakuoh , Takasu Kiyoshi , Minamino Tohru
Published: November 2020

Introduction:
Pulmonary hypertension (PH) is a syndrome of increased pulmonary artery pressure and often leads to death. Left heart diseases(LHD) are frequently complicated by PH (PH-LHD), classified group2. In particular, PH with heart failure with preserved LV ejection fraction (HFpEF) is higher prevalence metabolic syndrome and poor prognosis than LHD without PH. Tofogliflozin (TOFO) is SGLT2 inhibitor as a therapeutic agent for diabetes. Recent study revealed SGLT2 inhibitors have a beneficial effect on heart failure. However it has not been clarified that SGLT2 inhibitors affect PH-LHD. This study examined whether TOFO improved for PH-LHD.

Hypothesis:
We hypothesis TOFO has a protective effect for PH with HFpEF.

Methods:
We used two HFpEF mice models, induced by transverse aortic constriction (TAC) surgery and high fat diet (HFD). TAC model: C57BL/6J mice were subjected to TAC. Sham and TAC mice were treated with TOFO 3mg/kg in water by day or only water. After 4weeks, each mouse was measured physical data, Body weight (BW), Left ventricular weight (LV), Right ventricular weight (RV), right ventricular systolic pressure (RVSP), UCG, collected blood and urine glucose. HFD model: AKR/J mice fed a HFD for 20weeks. Regular diet and HFD mice were treated with TOHO 3mg/kg in water by day or only water. 20weeks later each mouse measured above data.

Results and Conclusions:
Mice treated with TOFO had significantly higher urine glucose concentrations. TAC induced left ventricular hypertrophy, increased HW/BW ratio and RVSP. However TAC+TOFO mice were reduced hypertrophy and LV/BW ratio than TAC group. Moreover TAC+TOFO mice were improved RV/LV ratio and RVSP (Figure). AKR/J+HFD groups substantially higher BW and occurred PH than RFD groups. In contrast with HFD, TOFO treated group ameliorated BW, RW/LW ratio, moreover normal RVSP. These results showed Tofogliflozin had a beneficial effect for PH with HFpEF.
Abstract 16314: Late Survival After Atrial Switch in Transposition of the Great Arteries: Results From a Multi-institutional Study
Authors: van Dissel Alexandra , Opotowsky Alexander , Aboulhosn Jamil , Kauling Martijn , Ginde Salil , Krieger Eric , Shah Sangeeta , Gupta Tripti , Rodriguez Fred , JOHN Anitha , Jaidzeka Sandra , Cotts Timothy , Stumpf Mary , Dwight Cindy , Woods Patty , Nicolarsen Jeremy , Sarubbi Berardo , Fusco Flavia , Antonova Petra , Fernandes Susan , Grewal Jasmin , Janzen Mikyla , CRAMER Jonathan , Khairy Paul , Gallego Pastora , O’Donnell Clare , Hannah Jane , Dellborg Mikael , Vonder Muhll Isabelle , Pylypchuk Stephen , Magalski Anthony , DeZorzi Christopher , Han Frank , Sammons Amanda , Kay Joseph , yeung elizabeth , Baker David , Celermajer David , Burchill Luke , Broberg Craig
Published: November 2020

Background:
Although several factors have been cited for risk stratification in patients with simple transposition of the great arteries (dTGA), no single predictor emerges consistently. We aimed to assess survival and determine factors associated with survival in a large cohort of dTGA adults with atrial switch.

Methods and Results:
We included 1,169 dTGA adults (median age 28.1 years, 38.7% female) under regular follow-up at 28 institutions between 2002 and 2019. The primary outcome was a composite of death, mechanical circulatory support (MCS) and heart transplant. During a median follow-up of 9.2 [IQR 5.5-14.2] years, 67 (5.7%) patients died, six (0.5%) patients underwent MCS and 21 (1.8%) had a heart transplant. Cumulative incidence of composite endpoint at 15 years was 12.8% [95% CI 9.8 - 15.7], see Figure). Median age at time of primary outcome was 39.5 [IQR 33.9 - 45.1] years. Leading causes of death were worsening of heart failure (34%), non-cardiac (21%) and sudden unexplained death (12%). In multivariable Cox analyses for baseline variables, age, VSD, ventricular arrhythmia and heart failure admission were each associated with increased risk of the outcome, whereas prior pacemaker (26% of patients) was not. New pacemaker implantation was performed in 107 (9.1%), ICD in 109 (9.3%), and cardiac surgery in 35 (3%) patients. Patients who died were more likely to develop arrhythmias, be admitted for heart failure or require surgery during follow-up.

Conclusion:
In this large contemporary cohort of dTGA adults after atrial switch, late survival was excellent and seemed to be determined by arrhythmia and heart failure-related complications. Few patients underwent advanced heart failure therapies.

Figure.
Cumulative incidence of the composite primary outcome (MCS, heart transplant or death) over a period of 15 years from first visit at an adult congenital heart disease clinic since 2002. Shading represents upper and lower 95% confidence limits.
Abstract 16348: Comparison of Heart Rate Variability, Physical Activity, and Fitness Parameters Between Healthy Women and Breast Cancer Survivors
Authors: Martínez-Rosales Elena , Hernández-Martínez Alba , Alcaraz-Ibáñez Manuel , López-Sánchez Laura , Díez-Fernández David Manuel , Soriano-Maldonado Alberto , G Artero Enrique
Published: November 2020

Introduction:
Breast cancer remains the most commonly type of cancer. Heart rate variability (HRV), a clinical indicator of autonomic dysfunction and premature mortality, has been found to be impaired in breast cancer survivors immediately after treatment and in the last stages of metastasis. Physical activity and fitness represent relevant health markers that might prevent some of the side effects following breast cancer treatment, so it would be of clinical interest assessing potential differences with healthy controls.

Hypothesis:
Compared to healthy women, breast cancer survivors are expected to show impaired HRV-derived parameters, as well as lower physical activity and fitness.

Methods:
This cross-sectional study included 20 women that survived breast cancer (post-operative period >2 years) and 20 healthy women controls, matched by age and BMI. Fitness evaluations included the modified Ruffier-Dixon test and handgrip strength. Moderate-to-vigorous physical activity (MVPA) was assessed through a self-reported questionnaire. Short-term HRV was measured using 5-minutes recording and were analyzed with Kubios Premium. Sample size was determined for two-tailed tests, statistical power of 0.8, effect size >0.7, and significance level of p<0.05. Between-groups differences were examined using Mann–Whitney U test and Student’s t-test, for normally and not-normally distributed variables, respectively.

Results:
Concerning HRV parameters, breast cancer survivors presented lower Very Low Frequency and Low Frequency, and higher Low Frequency/High Frequency ratio (all
p
<0.001), compared to controls. No statistically significant differences were observed in MVPA time (
p
=0.48) or estimated VO
2max
(
p
=0.24), although handgrip strength was decreased in cancer survivors (
p
=0.02).

Conclusions:
A cardiovascular imbalance in breast cancer survivors may be suggested in comparison to healthy age- and BMI-matched controls, as evidenced by reduced HRV after >2 years of post-operative treatment. In contrast, there were no differences in weekly MVPA or VO
2max
between groups, although muscular strength could still be affected. These results need to be contrasted by future long-term prospective research.
Abstract 16395: Soluble ST2 and Its Association With Echocardiographic Measures of Cardiac Structure
Authors: Gong Alexander O , Balac Nina , Patel Sagar V , Hwang Jennifer , McLeod Jennifer M , Grazette Luanda P
Published: November 2020

Background:
Soluble ST2 (sST2) has emerged as a powerful prognostic marker in chronic systolic heart failure with reduced ejection fraction (HFrEF). Elevated levels of sST2 are associated with adverse cardiac remodeling and fibrosis. We have previously described the prognostic value of sST2 collected from stable patients in the ambulatory setting and correlated it with long term clinical outcomes. However, few studies have demonstrated the association between sST2 levels and echocardiographic measures of cardiac structure and function as well as outcomes.

Hypothesis:
Baseline circulating levels of sST2, using the partition value of 35 ng/ml, will correlate with echocardiographic measures of cardiac chamber size and function in stable stage C patients in the ambulatory setting.

Methods:
Single-center, retrospective observational study of subjects presenting to an ambulatory heart failure (HF) clinic from July 2014 to December 2016. There were 156 subjects with stage C heart failure and a baseline sST2 level. For purposes of this analysis in HFrEF, we excluded patients with EF > 40% resulting in a study cohort of 103 subjects. The mean follow-up was 2.20 years ± 1.53 years. Analysis was performed with IBM SPSS Statistics 26. Discrete variables were expressed as counts (percentage) and were compared using the Chi-squared test. Mean differences of continuous variables were expressed as a mean ± standard deviation and compared using the unpaired Student’s
t-
test.

Results:
Patients who had baseline sST2 ≥ 35 ng/ml had a greater LA volume index (p=0.05) and RA area (p=0.01) compared to patients with sST2 < 35 ng/ml. Patients with sST2 ≥ 35 ng/ml had a mean LA volume index of 62.72 ± 30.28 ml/m
2
and RA area of 24.59 ± 7.87 ml/m
2
. We also found that sST2 ≥ 35 ng/ml was associated with increased risk for atrial arrhythmias (39.0% vs. 20.5%), a higher New York Heart Association classification (2.73 vs. 2.18), lower hemoglobin (11.5 vs 13.0), and lower systolic blood pressure (109.6 vs 124.8).

Conclusion:
In our study, subjects with sST2 levels ≥ 35 ng/ml was associated with increased atrial size by echocardiography, increased risk for atrial arrhythmia and higher NYHA class. These findings support the utility of sST2 for risk stratification in ambulatory patients with HFrEF.
Abstract 16727: Cardiac Complications of SARS CoV-2 Associated Multi-System Inflammatory Syndrome in Children (mis-c)
Authors: Harahsheh Ashraf S , SABLE Craig A , Loke Yue-hin , DeBiasi Roberta L , Olivieri Laura , Donofrio Mary T , Parikh Kavita , Berul Charles I , Austin Ashley , Bell Michael , Christopher Adam , Cross Russell R , Dham Niti , Frank Lowell , Kline Jaclyn N , Ronis Tova , Smith Karen L , Spurney Christopher , Srinivasalu Hemalatha , Wessel David L , Zhang Jing , Krishnan Anita
Published: November 2020

Introduction:
A novel pediatric disease, MIS-C, has emerged during the COVID -19 pandemic. The majority of cases were reported from European and Northeastern US centers. We present our experience of MIS-C with cardiac findings from a large tertiary pediatric cardiac center.

Methods:
We conducted a retrospective study of all MIS-C patients evaluated and treated from 03/29/2020 to 6/18/2020 at our center. Demographics, clinical, echo and ECG data were extracted from the echo database and EHR. Abnormal cardiac findings during the acute phase were defined as coronary artery abnormality (CAA), decreased ejection fraction (EF) and rhythm abnormality. CAAs were defined as dilation (z-score of > 2 to ≤ 2.49) or aneurysm (2.5 to < 5) as well as reviewed for qualitative changes.

Results:
32 children, 17 (53%) males have been treated for MIS-C. The median (IQR) age was 9 (7 - 13) years. Underlying medical conditions were noted in 9 (28%) patients including 2 with cardiac conditions (one with previous history of atypical Kawasaki Disease (KD) and one with previous history of pericardial effusion s/p pericardial window). Ten (31%) patients had abnormal cardiac findings; 4 had isolated CAA, 3 had combined CAA and low EF and 2 had isolated low EF. One patient had aneurysms in all 3 CA’s, 2 patients had abnormalities in 2 CA’s (LMCA and RCA aneurysms in 1 and LMCA aneurysm and LAD dilation in 1 patient), and 4 patients had single CAA (RCA dilation in 1, LAD aneurysm in 1, and LAD dilation in 2 patients). No patient with CAA had morphologic evidence of saccular or fusiform changes. CAA persisted on subsequent echo in 3 patients and normalized in 3 patients. EF normalized on subsequent echo in 3 patients. One of the patients with isolated low EF was also found to have intermittent high grade atrioventricular (AV) block. The 10
th
patient had normal echo but 1st degree AV block, sinus bradycardia, and long QTc. No arrhythmia was noted. No mortality occurred and overall length of stay was 13.6±9 days.

Conclusion:
Our MIS-C patients had a high rate of cardiac findings in the acute phase which exceeded rates historically observed in the setting of KD. Further long term study is needed to assess if the cardiac abnormalities persist, improve with immune modulation or are associated with major cardiac events.
Abstract 16734: Oral Nitrite Supplementation Improves Skeletal Muscle Mitochondrial Respiration and Cardiorespiratory Fitness in Older Adults With Heart Failure With Preserved Ejection Fraction
Authors: Shah Rohan , Coen Paul , Gladwin Mark T , Forman Daniel E
Published: November 2020

Introduction:
Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, especially among older adults. HFpEF is commonly associated with exercise intolerance and skeletal muscle weakening which likely contribute to functional decline. We studied the utility of nitrite (NO
2
) supplementation with the aim to augment skeletal muscle mitochondrial respiration.

Hypothesis:
NO
2
administered via oral supplements would be associated with improved mitochondrial respiration. Whereas prior studies with other oral and inhaled nitrate and NO
2
therapy in HFpEF patients have been inconsistent, we used novel NO
2
capsules that we hypothesized would achieve higher serum levels of nitrite and nitrate, and greater cellular and clinical benefits.

Methods:
A randomized, placebo-controlled pilot trial to study the utility of oral sodium (Na) NO
2
over 4 weeks in an older population (≥70 years) was done. Participants received 20 or 40 mg Na-NO
2
supplements 3 times daily based on their hemodynamic responses. Pre- and post-NO
2
intervention participants underwent biopsies of the vastus lateralis muscle with associated assessments of mitochondrial respiration in permeabilized fibers and also completed cardiopulmonary exercise test.

Results:
15 participants were randomized and 13 completed the interventions (n=6 on NO
2
, n=7 on placebo, 69% men, mean age 75.7 years, range 70-91). Post-intervention serum NO
2
level increased (+0.61±0.67 μmol on NO
2,
+0.25±0.15 on placebo). Ex-vivo analysis of mitochondrial respiration showed increased O
2
consumption in muscle (+27.1±27.4 pmol/(s*mg) on NO
2
, -11.7±11.3 on placebo). Rated perceived exertion during steady-state walking decreased (-1.2±2.0 on NO
2,
+0.2±1.6 on placebo). Peak oxygen uptake (VO
2
) increased (+1.4±5.2 ml/kg/min on NO2, -3.4±5.2 on placebo).

Conclusion:
Our study demonstrated efficacy and potential clinical utility of oral NO
2
supplementation in older HFpEF patients with an internally consistent physiologic composite of improved skeletal muscle mitochondrial respiration in association with improved cardiorespiratory fitness and diminished perceived exertion during steady-state walking. Clinical implications are auspicious and further research is indicated.
Abstract 16738: Association Between First and Second Trimester Maternal Screening Biochemistry, Ultrasound, and Fetal Brain Growth in Presence of Fetal or Maternal Congenital Heart Disease
Authors: Sharma Aman , Lewis Emma , Gray Gabrielle , Maldonado Jennifer R , Knoedel Diana L , Lancial Colleen , Aldoss Osamah , Santillan Donna A , Porayette Prashob
Published: November 2020

Introduction:
Newer research has highlighted significant neurological impairments in children and adults with congenital heart disease (CHD). The more severe the heart defect, the higher the neurologic impairment. Pregnancies complicated by fetal or maternal CHD carry a higher risk of placental abnormalities. We studied the association between pregnancy hormonal levels and fetal head and body growth.

Hypothesis:
Placental dysfunction in pregnancies with fetal or maternal CHD alters pregnancy hormonal levels affecting fetal brain and somatic growth.

Methods:
We performed a retrospective case-control study on pregnant women (year 2010-2019) at the University of Iowa. Only women with first and/or second trimester prenatal screening (ultrasound and blood test) were included. Pregnancies with fetal chromosomal abnormalities, multiple gestation, maternal diabetes, smoking, or hypertension were excluded. Pregnancies were either healthy controls (n=36), women with CHD (MCHD; n=26), or fetus with CHD (FCHD; n=23). Pregnancy hormonal levels, ultrasound findings, and fetal/neonatal growth percentiles and/or z-scores data were analyzed.

Results:
Women with CHD were younger (p=0.004) with increased fetal nuchal translucency (p=0.003) compared to controls. Women in MCHD (p=0.02) and FCHD (p=0.02) group delivered earlier than controls. FCHD had significantly lower pregnancy associated plasma protein-A (PAPP-A) levels than controls (p=0.04). The groups had no difference in the second trimester fetal head circumference (HC) and femur length. FCHD group had significantly smaller HC percentile (p=0.03) and z-scores (p=0.03) at birth than controls. Both FCHD and MCHD had smaller birth weight and length compared to controls. However, only FCHD group demonstrated significantly lower HC to birth weight ratio (p=0.01). The controls had a positive correlation between human chorionic gonadotropin level and head circumference z-score at birth (r=0.34;p=0.053).

Conclusions:
Pregnant women with CHD have increased fetal nuchal translucency and deliver at earlier gestational age. Women with fetal CHD have smaller neonatal head and body size at birth with associated low PAPP-A level early in their pregnancy probably related to placental dysfunction.
Abstract 16770: The Epigenetic Modifier EP300: A New Corner Stone in the Regulation of Both Vascular Remodeling and Right Ventricle Failure in Pulmonary Arterial Hypertension
Authors: Bourgeois Alice , Lemay Sarah-Eve , Grobs Yann , romanet Charlotte , Omura Junichi , Toro Victoria , Nadeau Valerie , Tremblay Eve , Breuils-Bonnet Sandra , Provencher Steeve , BOUCHERAT Olivier , Bonnet Sebastien
Published: November 2020

Introduction:
Pulmonary Arterial Hypertension (PAH) is characterized by excessive proliferation and resistance to apoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs), leading to progressive increases in pulmonary vascular resistance, and ultimately right ventricular (RV) failure and death. Thanks to omics technologies, we made tremendous progress in understanding gene misregulation during disease processes and identified the epigenetic factor EP300 as a critical player in pathological processes like proliferation/apoptosis and hypertrophy/fibrosis all of which are critical features of both PA remodeling and RV failure in PAH. We hypothesized that EP300 is upregulated in PAH and contributes to both PA remodeling and RV failure.

Methods and Results:
By Western blot (WB) and immunofluorescence (IF), we found that EP300 is up-regulated in isolated PASMCs and distal PAs from PAH patients (n=11-14) compared to controls (n=8-10) (p<0.01). Similar results were observed in 3 PAH animal models, namely the monocrotaline (MCT), the Sugen/Hypoxia (Su/Hx) and the Fawn-Hooded rat (FHR) (p<0.05). In vitro, pharmacological inhibition of EP300 using CCS-1477 reduces PAH-PASMC proliferation (Ki67 labeling & WB PCNA; p<0.05) and resistance to apoptosis (Annexin V assay & WB Survivin; p<0.05). These effects were confirmed at the molecular level by RNA-Seq analysis. In addition, increased EP300 expression was observed in hypertrophied and failed RV from PAH patients, as well as in rats injected with MCT or subjected to pulmonary artery banding (WB, p<0.05). In animal models, EP300 negatively correlates with CO and positively correlates with RVEDP, cardiomyocyte surface area and fibrosis. Finally, we demonstrated that inhibition of EP300 using CCS-1477 or SGC-CBP30 significantly improved established PAH (right heart catheterization) in two animal models (MCT and FHR).

Conclusion:
EP300 upregulation contributes to both pulmonary vascular remodeling and RV dysfunction seen in PAH and its inhibition represents a promising therapeutic avenue.
Abstract 17102: Lower Rate of Device-Related Thrombosis in Watchman Patients Undergoing a Genotype-Tailored Antithrombotic Strategy
Authors: Della Rocca Domenico G , Horton Rodney , Gianni Carola , Di Biase Luigi , TRIVEDI CHINTAN G , Mohanty Sanghamitra , Tarantino Nicola , Bassiouny Mohamed , Al-ahmad Amin , Burkhardt David , Gallinghouse G , Sanchez Javier , Natale Andrea
Published: November 2020

Introduction:
Loss-of-function (LOF) polymorphisms of the cytochrome P450 2C19 (CYP2C19) gene are associated with reduced hepatic bioactivation of clopidogrel.

Hypothesis:
To evaluate the prevalence of LOF polymorphisms of CYP2C19 and the incidence of device-related thrombosis (DRT) when clopidogrel is replaced with half dose novel oral anticoagulant (NOAC) in patients with reduced clopidogrel metabolism.

Methods:
Consecutive Watchman patients were genotyped for CYP2C19 polymorphisms. Patients with reduced clopidogrel metabolism received half dose NOAC plus aspirin during the “dual antiplatelet therapy (DAPT) phase” post-Watchman implantation (between 45 days and 6 months). The incidence of DRT among genotyped patients (Group I, n=401) and a control group without genotypization (Group II, n=357) which received standard DAPT is reported.

Results:
Overall, 758 Watchman patients were included (mean age: 75±8 yrs, 63% males, CHA
2
DS
2
-VASc: 4.6±1.5; HAS-BLED: 3.2±1.1). Of the 401 Group 1 patients, 25.69% (n=103) were reduced clopidogrel metabolizers. In 87.4% of them, clopidogrel was replaced with half-dose NOAC during the “DAPT phase” post-Watchman implantation whereas 12.6% received ASA plus full-dose NOAC due to the presence of a significant peri-device leak. During the “DAPT phase”, DRT was documented in 1 (0.2%) patient of Group I and 7 (1.96%) patients of Group II (p=0.029). On multivariate analysis, a genotype-tailored antithrombotic strategy was associated with a significant reduction in DRT (odds ratio: 0.11; 95% confidence interval: 0.01 - 0.98; p-value: 0.048).

Conclusions:
Approximately 25% of our Watchman patients had clopidogrel resistance. Substitution of clopidogrel with half dose NOAC in reduced clopidogrel metabolizers significantly reduced the incidence of DRT.