bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17030: Stress-Related Neurobiological Activity Contributes to the Link Between Cardiovascular Polygenic Risk Score and Myocardial Infarction
Authors: Abbasi Taimur , Abohashem Shady , Dar Tawseef , Ghoneem Ahmed , Naddaf Nicki , Zureigat Hadil , Fahed Akl C , Aragam Krishna , Khera Amit V , Osborne Michael , Tawakol Ahmed A
Published: May 2021

Introduction:
A polygenic risk score for coronary artery disease (PRS
CAD
) integrates information from many sites of DNA variation into a single metric of inherited susceptibility. Heightened metabolic activity of the amygdala (AmygA), a stress-associated brain center, associates with increases in leukopoietic activity, atherosclerosis and CVD risk. We hypothesized that genes included in the PRS
CAD
link to MI in part by encoding for heightened stress-associated neurobiological activity. Accordingly, we tested whether CVPRS associates with heightened AmygA as a contributing factor linking high CVPRS and CVD events.

Methods:
Individuals (N=16821, median age (IQR): 63 (52, 74) years, 46% male) were identified from the Partners Biobank where genome-wide PRS
CAD
and principle components of ancestry (PCI) were calculated. Using validated
18
FDG-PET/CT imaging methods, AmygA was measured in individuals with prior clinical imaging (N=854). MI incidence was derived using International Classification of Diseases (ICD) diagnoses. Traditional CVD risk factors and psychiatric history were obtained using ICD codes and questionnaires and were used for covariable adjustments. Linear and logistic regression were employed.

Results:
A total of 2046 (12.1%) participants experienced an MI. PRS
CAD
associated with increased AmygA after adjusting for age and sex (β [95% confidence interval (CI)]: 0.099 [0.015, 0.183], p=0.021) as well as increased MI incidence (odds ratio (OR) [95% CI]: 1.208 [1.120, 1.302], p<0.001) (
Table 1, Figure 1
). Concurrently, AmygA associated with increased MI incidence in adjusted analyses (OR [95% CI]: 1.451 [1.061, 1.983], p=0.003).

Conclusion:
High PRS
CAD
associates with higher AmygA and AmygA in-turn associates with MI. These findings suggest increased stress-related neurobiological activity may contribute to the link between PRS
CAD
and MI.
Abstract 17036: Cardiomyocyte Krüppel-Like Factor 5 Regulates Ceramide Biosynthesis and Promotes Systolic Dysfunction in Ischemic Heart Failure
Authors: Hoffman Matthew K , Kyriazis Ioannis , Palioura Dimitra , Cimini Maria , Rajan Sudarsan , Gao Erhe , Nikolaidis Nikolas , Schulze Christian , Goldberg Ira J , Kishore Raj , Yang Vincent W , Bannister Thomas , Bialkowska Agnieszka , Selzman Craig , Drakos Stavros G , Drosatos Konstantinos
Published: May 2021

Introduction:
Our lab previously showed that cardiomyocyte Krüppel-like factor (KLF)-5 regulates cardiac fatty acid oxidation. Various studies have associated heart failure with altered cardiac fatty acid oxidation and lipotoxicity.

Hypothesis:
Aberrant regulation of KLF5 contributes to pathophysiology and metabolic perturbations in ischemic heart failure.

Methods and Results:
Analysis of KLF5 mRNA and protein levels in human ischemic heart failure samples and in rodent models 2- and 4-weeks post-myocardial infarction (MI) showed significantly increased KLF5 expression. To investigate the involvement of KLF5 in the pathophysiology of ischemic heart failure, we treated mice that were subjected to MI with a pharmacological KLF5 inhibitor (ML264). ML264 increased ejection fraction and reduced diastolic volume. Likewise, mice with cardiomyocyte-specific KLF5 deletion (αMHC-KLF5
-/-
mice) were protected from ischemic heart failure. Lipidomic analysis by LC-MS/MS showed that αMHC-KLF5
-/-
mice after MI had lower myocardial ceramide levels compared with control mice with MI. Accordingly, the expression of cardiac SPTLC1 and SPTLC2, which regulate de novo ceramide biosynthesis, was higher in control mice with MI and lower in αMHC-KLF5
-/-
mice with MI. KLF5 overexpression in HL1 cardiomyocytes increased SPTLC1 and SPTLC2 mRNA and protein levels. ChIP-qPCR and luciferase promoter assays showed that KLF5 activates the promoters of these genes via direct binding. To assess the transcriptional effects of KLF5 independent from other changes that occur with MI, we generated a mouse model of inducible (Dox-ON), cardiomyocyte-specific expression of KLF5 (αMHC-rtTA-KLF5). Systolic dysfunction was evident 2-weeks following KLF5 induction. Heart tissue from these mice exhibited increased SPTLC1 and SPTLC2 mRNA and protein levels, and inhibition of SPT using myriocin suppressed myocardial ceramide levels and alleviated systolic dysfunction.

Conclusions:
KLF5 is induced during the development of ischemic heart failure in humans and mice, and stimulates expression of SPTLC1 and SPTLC2 that promote ceramide biosynthesis. KLF5 inhibition emerges as a novel therapeutic target to protect against ischemic heart failure.
Abstract 17043: Predictors of Length of Stay Following Catheter Ablation of Atrial Fibrillation
Authors: Allam Sahitya , Harmon Evan , Mangrum James M , Haines David , Mehta Nishaki K
Published: May 2021

Background:
Catheter ablation (CA) of atrial fibrillation (AF) is a safe and effective management strategy for symptomatic AF. Traditionally, patients are observed overnight following CA, but recent data has suggested same day discharge may be feasible with low risk of complications. However, little data is available to predict length-of-stay (LOS) in AF patients undergoing CA.

Methods:
We conducted a single-center retrospective analysis of 200 consecutive patients undergoing CA at a tertiary care academic center from July 2017 through June 2018. Baseline demographic data, echocardiographic data, procedural characteristics and postprocedural outcomes were collected through chart review. Multivariate linear regression modeling was used to identify factors associated with increased LOS (LOS > 1 day).

Results:
Among 200 patients, 11.5% (23) of patients had LOS > 1 day (Group B) while the rest were discharged after overnight stay (Group A). The mean ages were similar in Groups A and B (64.8 years and 64.9 years respectively, p = 0.98). The mean LOS was 1.44 ± 1.83 days. Higher proportions of hypertension (p = 0.02), diabetes (p = 0.1), baseline loop diuretic use (p < 0.001), EF < 50% (p < 0.001), increased LA diameter (p = 0.01), longer procedure time (p = 0.03), and recurrent AF following CA (p < 0.001) were noted in Group B patients (Table 1). A multivariate linear regression model demonstrated that procedure time (p = 0.02) and LA diameter (p = 0.04) were positively associated with increased LOS.

Conclusion:
Identifying risk factors for increased LOS in patients undergoing CA of AF may guide appropriate patient selection for same day discharge.

Table 1. Comparison of patients with overnight observation (Group A) and LOS > 1 day (Group B) following AF ablation.
Abstract 17054: Age-Based Variation in Temporal Trends for Takotsubo Syndrome Differ by Sex
Authors: Pattisapu Varun , HAO HUA , Nguyen Trevor Trung , Merz Noel B , Cheng Susan
Published: May 2021

Background:
Takotsubo syndrome (TTS) has been increasingly recognized in the United States. Since its initial description in 1990, diagnosed cases of TTS have been rising over time and the extent to which this trend differs by sex and across age is unclear.

Methods:
Using the National Inpatient Sample (NIS) data from 2006 to 2014, we identified hospitalizations with either a primary or secondary diagnosis of TTS. We analyzed these data stratified by sex and by age groups: <=50 years, 50 to 74 years, and >=75 years. For the trend measurements, the sampling effects were accounted for by applying NIS survey weights using the SAS PROC SURVEYMEANS procedure.

Results:
We identified a total of N=18,051 TTS cases over the study period, most of which were experienced by women (89.1%). The frequency of diagnosed TTS cases progressively increased from 2006 to 2014 in both women and men, across all age groups. However, the frequency of diagnosed TTS cases increased at a markedly more rapid rate in women compared to men (rate of change of 182.7 per million hospitalization per year in women vs 44.9 per million hospitalization per year in men, P<0.0001). The rate of increase in annual case diagnosis was particularly high for women aged 50 years or older compared to younger women or men of any age group (

Figure

).

Conclusion:
Our results demonstrate that while increasing recognition of TTS may be contributing to a steady rise of case diagnoses per annum in both sexes and across age groups, the rate of case diagnosis increase is particularly rapid in middle-aged and older women. Further research is needed to validate and investigate the potential determinants underlying our findings.
Abstract 17062: Atherosclerotic Cardiovascular Disease Risk in South Asians by Statin Use: Insights From a Large Integrated Healthcare Delivery System
Authors: Mantri Neha M , Merchant Maqdooda , Rana Jamal S , Parikh Rishi , Go Alan S , Pursnani Seema
Published: May 2021

Introduction:
South Asian ethnicity is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk and has been identified as a “risk enhancer” in the 2018 ACC/AHA Guideline on the Management of Blood Cholesterol.

Hypothesis:
An increased use of statins has been recommended since implementation of the 2013 ACC/ AHA Pooled Cohort Equation (PCE); however, the impact of statins on ASCVD outcomes in South Asians is not well understood. We aim to identify the accuracy of 10-year ASCVD risk prediction by the PCE, based on statin use, in a South Asian cohort.

Methods:
This is a retrospective cohort study of members within Kaiser Permanente Northern California without existing ASCVD, age range 30-70, for whom lipid panel, ethnic data, and 10-year follow up were available. ASCVD events were defined as acute myocardial infarction, ischemic stroke, and cardiovascular death. The cohort was stratified by statin use: never, at baseline and follow-up and only during follow-up. Predicted probability of ASCVD, using the PCE were calculated and compared to the observed for each ASCVD risk category: low <5.0%, borderline 5.0-7.5%, intermediate 7.5-<20.0%, and high >=20.0%.

Results:
A total of 1,835 South Asian patients were included. ASCVD risk was underestimated by the PCE across all risk categories and statin groups. The greatest disparity was seen in the low-risk ASCVD risk group; entire cohort: 1.8 vs 4.9%, p<0.0001; on statin at baseline and follow-up: 2.58 vs 8.43%, p<0.0001; on statin during follow-up only: 2.18 vs 7.77%, p<0.0001; and never on statin: 1.37 vs 2.09%, p=0.1175 (Figure 1). The absolute risk difference in ASCVD outcomes between the cohort never on statins to those on statins during follow up was 0.73%, 3.31%, and 6.67% in the borderline, intermediate, and high-risk groups, respectively.

Conclusions:
In a large, community-based South Asian cohort, the PCE underestimated risk in South Asians, who were taking statins, in the low ASCVD risk category.
Abstract 17065: Performance of Cardiovascular Disease Risk Scores to Identify Coronary Artery Calcium Burden in Retired National Football League Players
Authors: Smith Genevieve E , Drezner Jonathan A , Fernandez Camilo , Stewart Gregory W
Published: May 2021

Introduction:
Coronary artery calcium (CAC) is a robust predictor of coronary events in asymptomatic individuals with latent atherosclerotic cardiovascular disease (CVD). While evidence suggests CAC scoring may augment traditional CVD risk scores in clinical decision making, evidence is limited on the compared ability of CVD risk scores to identify the degree of coronary atherosclerosis as quantified by absolute CAC, particularly in former elite athlete populations. We investigated this in a cohort of retired National Football League (NFL) players.

Methods:
We analyzed data on 752 retired NFL players (aged 55.2 ± 9.0 years, 53.7% African-American] that underwent health screening and CAC scoring with the NFL Player Care Foundation. Three 10-year CVD risk scores were compared: Framingham Coronary Heart Disease (FCHD), Framingham CVD (FCVD), and Atherosclerotic CVD Risk Pooled Cohort Equations (PCE). Receiver operating characteristic curves were fitted in 3 models: FCHD (Model 1), FCVD (Model 2), and PCE (Model 3, used as reference based on 2013 AHA guidelines). Contrast analyses identified the model with highest discriminative ability (c statistic) versus CAC = 0 for each CAC score category: >0 and <100, 100-400, and >400.

Results:
Compared to PCE
,
FCVD exhibited the highest discriminative ability for CAC > 0 and < 100 (
c statistic
0.7071 vs 0.6706, p<0.0001), while FCHD had the lowest for both CAC 100-400 (
c statistic
0.7198 vs 0.7664, p=0.0165) and CAC >400 (
c statistic
0.7728 vs 0.8460, p<0.0001). No additional differences were identified (Figure 1).

Conclusion:
Traditional CVD risk scores differ in performance to predict absolute CAC among retired NFL players, underscoring a need for refinement of coronary event risk prediction models to enhance the ability of such models to identify, specifically, low CAC, as even low CAC burden confers increased risk compared to CAC absence. This may include accounting for elite athlete-specific characteristics.
Abstract 17075: Impact of Peripheral Artery Disease on Outcomes Following Admission for Cardiogenic Shock
Authors: Mihatov Nino , Yeh Robert W , Choi Eunhee , Shen Changyu , Parikh Sahil A , Rosenfield Kenneth , Secemsky Eric A
Published: May 2021

Introduction:
Contemporary in-hospital mortality rates for patients presenting with acute myocardial infarction (AMI) and cardiogenic shock (CS) remain as high as 50%. The impact of comorbid lower extremity peripheral artery disease (LE-PAD) is unknown.

Hypothesis:
LE-PAD is associated with higher morbidity and mortality in patients presenting with CS and AMI.

Methods:
Medicare beneficiaries hospitalized with CS related to AMI from 10/2015-6/2017 were identified. PAD status was defined by the inpatient billing codes present in the year prior to presentation. Outcomes included in-hospital mortality, amputation, peripheral revascularization, and 6-month mortality. Adjusted regression models were used to evaluate outcomes. A subgroup analysis included patients requiring mechanical circulatory support (MCS).

Results:
Among 45,144 patients, 5.9% (N=2,651) had LE-PAD. The average age was 77.8±7.9, 59.8% were male and 83.0% were white. Cumulative in-hospital mortality was 46.8%, with greater risk among LE-PAD patients (55.2% vs 46.3%; adjusted OR 1.52, 95% CI 1.39-1.65). LE-PAD patients also had greater adjusted risk of in-hospital amputation (1.5% vs 0.2%; OR 3.23, 95% CI: 2.16-4.83), peripheral revascularization rates (1.4% vs 0.4%; OR 1.54, 95% CI: 1.06-2.23), and 6-month mortality (43.2% vs 23.7%; HR 2.06, 95% CI: 1.80-2.35). MCS was less frequently utilized in LE-PAD (20.1% vs. 38.1%, p<0.01). Adjusted in-hospital mortality, amputation and peripheral revascularization rates were comparable between LE-PAD and non-LE-PAD patients who received MCS. Non-MCS LE-PAD patients had a 2.28 fold higher adjusted 6-month mortality compared with MCS LE-PAD patients (95% CI 1.60-3.11; Figure).

Conclusions:
Comorbid PAD is associated with worse limb outcomes and mortality among patients with AMI and CS. Although MCS was less likely to be used in LE-PAD patients, in-hospital mortality and limb complication rates were comparable to non-LE-PAD MCS patients.
Abstract 17076: Empowering Telemetry Technicians to Call Code Blue
Authors: McCoy Cody , Keshvani Neil , Warsi Maryam , Chu Eugene , Hegde Anita
Published: May 2021

Background:
Delays in treatment of in-hospital cardiac arrest (IHCA) events are associated with lower survival and poor neurologic outcomes. With centralized telemetry, telemetry technicians need to notify nursing staff of life-threatening arrhythmias immediately for nursing to verify a patient's clinical status and determine whether code blue activation is necessary. Delays in this verification lead to delays in code activation, which can in turn lead to increased morbidity and mortality.

Objective:
We sought to assess the impact of empowering telemetry technicians to activate code blues on IHCA code survival, survival to discharge, time to cardiopulmonary resuscitation (CPR), and inappropriate code activation.

Methods:
We implemented a quality improvement protocol September 1, 2016 at Parkland Memorial Hospital, a 900-bed, urban, safety-net hospital, in Dallas, Texas to empower telemetry technicians to call code blue directly for the following life-threatening arrhythmias: ventricular fibrillation, sustained ventricular tachycardia of greater than 30 seconds, asystole, or bradycardia less than 30 beats/minute. We performed a retrospective chart review of all IHCA in patients on centralized telemetry at Parkland for one year prior to the intervention and three years post intervention to look at code survival and survival to discharge. Secondary outcomes were time to CPR and inappropriate code activation.

Results:
The pre intervention code survival was 12/20 (60.0%) and the post intervention code survival was 46/55 (83.6%) (p=0.03). The pre intervention survival to discharge was 3/20 (15.0%) and the post intervention survival to discharge was 21/55 (38.2%), (p=0.0585). The time to CPR, in seconds, was 180 versus 120 (p=0.58) for pre and post intervention non-PEA codes. There were 0 inappropriate code activations post intervention.

Conclusions:
Empowering telemetry technicians to activate code blue for general ward patients on centralized telemetry showed a significant improvement in code survival and a trend in survival to discharge. Importantly, there were no inappropriate code activations by telemetry technicians, highlighting the safety of this intervention.
Abstract 17098: Liver Fibrosis and Associated Cardiovascular Disease Risk and Its Predictors Among US Adults With and Without Diabetes
Authors: Wong Nathan D , Bang Matthew , FAN WENJUN , Espinueva Aprille
Published: May 2021

Background:
Liver fibrosis is a complication of non-alcoholic fatty liver disease (NAFLD) and is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. Whether this risk may be enhanced in persons with pre-diabetes (pre-DM) or diabetes (DM), however, is not established. We examined the association of liver fibrosis with estimated ASCVD risk and its predictors according to DM status.

Methods:
We studied 30,895 adults (3,983 or 12.9% with DM) from the National Health and Nutrition Examination Surveys 1999-2014 with liver function measures to calculate FIB-4 scores; values of 1.3-2.67 and >2.67 indicated a moderate and high probability of advanced fibrosis, respectively. We studied the prevalence high FIB-4 scores in those with and without pre-DM and DM and the 10-year ASCVD risk based on the ACC/AHA Pooled Cohort Risk Calculator in persons without known ASCVD. In addition, multiple logistic regression examined predictors of high FIB-4 scores.

Results:
The prevalence of FIB-4 scores of 1.3-2.67 and >2.67 ranged from 17.8% and 1.5% in those without pre-DM/DM, 29.9% and 2.5% in those with pre-DM, and 35.3% and 3.5% in those with DM, respectively (p<0.0001). The figure shows the 10-year ASCVD risk by FIB-4 scores and presence of pre-DM and DM. Multivariable indicators of a FIB-4 score >2,67 were age (odds ratio [OR]=3.0 / 10 years), female sex (OR=0.53), non-Hispanic Black ethnicity (OR=2.0), waist circumference (OR=0.76/SD), alcohol use (OR=1.5), and NALFD (OR=3.3) in those without DM, and age (OR=2.2/10 years), female sex (OR=0.48), systolic blood pressure (1.4/SD), diastolic blood pressure (0.76/SD), and current smoking (OR=2.2) in those with DM (all p<0.05 to p<0.0001).

Conclusions:
Advanced fibrosis is more prevalent in those with vs. without DM. The presence of DM with higher FIB-4 scores is associated with especially high estimated ASCVD risks warranting increased efforts to address prevention and treatment of liver fibrosis.
Abstract 17301: Safety of Direct Oral Anticoagulants Compared to Warfarin for Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis
Authors: Hage Ali , Dolan Daniel , Nasr Viviane G , Castelo-Branco Luis , Motta-Calderon Daniel , Ghandour Hiba , Papatheodorou Stefania , Chu Michael W
Published: May 2021

Introduction:
The evidence for use of direct oral anticoagulants (DOACs) in the management of post-operative cardiac surgery atrial fibrillation (POAF) is limited and mostly founded on clinical trials that excluded this patient population.

Hypothesis:
We performed a systematic review and meta-analysis of clinical trials and observational studies to evaluate the hypothesis that DOACs are safe compared to warfarin for the anticoagulation of patients with POAF.

Methods:
We searched PubMed, EMBASE, Web of Science, clinicaltrials.gov, and the Cochrane Library for clinical trials and observational studies comparing DOAC with warfarin in patients ≥18 years old who had post-cardiac surgery atrial fibrillation. Primary outcomes included stroke, systemic embolization, bleeding, and mortality, with secondary outcome of hospital readmission. We performed a random-effects meta-analysis.

Results:
We found 3 clinical trials, 1 prospective and 12 retrospective cohort studies eligible for inclusion with a total of 10,538 patients (3,207 DOAC patients and 7,331 warfarin patients). The meta-analysis for the primary outcomes showed significantly lower risk of stroke with DOAC use (6 studies, 7143 patients, RR 0.64; 95% CI 0.50 to 0.81, I2: 0.0%) compared to warfarin, a trend towards lower risk of systemic embolization (4 studies, 7289 patients, RR 0.64, 95% CI 0.41 to 1.01, I2: 31.99%) and similar risks of bleeding (14 studies, 10182 patients, RR 0.91; 95% CI 0.74 to 1.10, I2: 26.6%) and mortality (12 studies, 9843 patients, relative risk [RR] 1.01; 95% CI 0.74 to 1.37, I2: 26.5%) The secondary outcome of hospital readmission had similar risk between groups.

Conclusions:
Current evidence suggests that DOACs, compared to warfarin, in the management of atrial fibrillation after cardiac surgery is associated with lower risk of stroke and a strong trend for lower risk of systemic embolization, and no evidence of increased risk for hospital readmission, bleeding or mortality.
Abstract 17309: Scope and Determinants of Nonfinancial Barriers to Healthcare Access in Individuals With Atherosclerotic Cardiovascular Disease
Authors: Acquah Isaac , Valero-Elizondo Javier , Cainzos Achirica Miguel , Singh Rahul , Shah Karan , Hyder Maryam , Nasir Khurram
Published: May 2021

Introduction:
Barriers to healthcare - financial and nonfinancial - may result in unmet health needs and adverse outcomes. Despite this, the nonfinancial barriers to care among adults with atherosclerotic cardiovascular disease (ASCVD) is poorly defined in the US. We aimed to explore the scope and determinants of nonfinancial barriers to care among individuals with ASCVD.

Methods:
We analyzed data from the 2013-17 National Health Interview Survey (NHIS). We included adults with self-reported ASCVD (heart attack, angina, and/or stroke). Nine key variables in the NHIS that represent nonfinancial barriers to healthcare were assessed as absent/present, and participants were classified as having 0-1, 2, or ≥3 barriers. Multinomial logistic regression (using 0-1 nonfinancial barriers as reference) was used to evaluate the relationship between various sociodemographic factors, and an increasing number of nonfinancial barriers.

Results:
Of all the 15,758 adults with ASCVD (8.1% annually in the US; representing 19.6 million), 23.4% reported having at least one nonfinancial barrier to care while 4.9% reported 3 nonfinancial barriers. In a multivariable multinomial logistic regression, after stratifying by age, individuals from low-income families had an almost 2-fold relative prevalence of 3 nonfinancial barriers (
Figure)
. In the elderly, however, lack of insurance was the strongest predictor (relative prevalence ratio of 6.51 [95% confidence interval; 2.25, 18.87]) of having ≥3 barriers.

Conclusion:
Among adults with ASCVD, the relative prevalence of ≥3 nonfinancial barriers was low (4.9%) with low-income being the only modifiable predictor of reporting ≥3 nonfinancial barriers and lack of insurance being the strongest predictor in the elderly. Addressing financial barriers to healthcare may help alleviate these nonfinancial barriers.
Abstract 17314: Flow-Mediated Susceptibility of Cerebral Endothelia to Sars-CoV-2 Infection Using Endothelialized 3D Human Vascular Models
Authors: Kaneko Naoki , Guo Lea , An Jennifer , Kakarla Visesha , Hinman Jason D
Published: May 2021

Introduction:
The clinical syndrome associated with Sars-CoV-2 infection is associated with an increased rate of cerebrovascular events, predominantly ischemic stroke. Direct viral invasion of the cerebral endothelium could be a significant driver of Sars-CoV-2-mediated stroke through expression of ACE2 and viral entry co-factors including TMPRSS2. Prior work indicates that ACE2 mRNA and protein are expressed in the endothelial cells of the brain, yet the effect of flow-mediated phenomena on ACE2 expression and the susceptibility of human cerebral endothelia to Sars-CoV-2 infection is unknown.

Methods:
3D printed models of the human middle cerebral artery were endothelialized with either human umbilical vein endothelial cells (HUVECs) or human brain microvascular endothelial cells (HBMECs). Endothelialized models were subjected to 3D rotational perfusional culture at variable pulsatile flow rates (0-22.5 dynes/cm
2
). ACE2 and TMPRSS2 expression were measured by Taqman qPCR. Biotinylated recombinant Sars-CoV-2 S protein was used to judge regional vessel binding of virus using confocal microscopy.

Results:
In 3D models endothelialized with either HUVECs or HBMECs, ACE2 mRNA expression is significantly modulated by vessel diameter and the presence of of flow (15 dynes/cm
2
) (p<0.0001 by two-way ANOVA). Pulsatile flow drives ACE2 expression more robustly in HUVECs than in HBMECs (11.5-fold vs. 4.9-fold; p<0.001). Higher flow rates (22.5 dynes/cm
2
) produced further increases in ACE2 expression in both cell types. Gene expression analysis demonstrated no detection of the Sars-CoV-2 viral entry co-factor TMPRSS2 in HBMECs. Flow-mediated ACE2 expression was associated with binding of recombinant Sars-CoV-2 S protein to the vessel wall suggesting direct cerebrovascular susceptibility to Sars-CoV-2.

Conclusion:
The Sars-CoV-2 cellular receptor ACE2 is expressed by human cerebral endothelia in a flow-dependent manner. Cerebral vessels are susceptible to Sars-CoV-2 infection and bind viral S protein under flow conditions but likely requires unique co-factors for viral entry. Identification of the molecular mechanisms triggered by Sars-CoV-2 infection in brain vasculature can alleviate the burden of stroke associated with COVID-19.
Abstract 17316: Association Between Time From Atrial Fibrillation Diagnosis to First Catheter Ablation With Long-Term Clinical Outcomes: Insights From the UC San Diego AF Ablation Registry
Authors: Mylavarapu Praneet , Aldaas Omar M , Malladi Chaitanya , Lupercio Florentino , Han Frederick , Hoffmayer Kurt S , Krummen David E , Ho Gordon , Raissi Farshad , Feld Gregory , Hsu Jonathan C
Published: May 2021

Background:
While the optimal timing for atrial fibrillation (AF) ablation is unknown, several studies have reported increased freedom from atrial arrhythmias among persistent AF patients with shorter time to first ablation after diagnosis. However, these studies have only examined two-year post-ablation outcomes.

Methods:
We performed a retrospective study of all patients who underwent first-time radiofrequency catheter ablation enrolled in the UC San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AAD). Median follow-up duration was 3.9 (0.4 - 6.8) years. Patients were categorized into quartiles by time from diagnosis of AF to first ablation (0-250, 251-855, 856-2200, and >2200 days respectively).

Results:
Among 534 total patients, the median diagnosis-to-ablation time was 2.3 years (25th-75th percentiles 0.7-6.0 years). At 5 years post-ablation, freedom from atrial arrhythmia significantly decreased as time to ablation increased in both paroxysmal and persistent AF (Parox: 50.5%, 46.8%, 35.6%, 36.6%, p-trend=0.042; Persist: 36.9%, 23.6%, 16.3%, and 22.6%, p-trend<0.01 for 1st, 2nd, 3rd, and 4th quartiles respectively). After adjustment, clinically significant differences in freedom from atrial arrhythmia were found in both paroxysmal and persistent AF when compared to the 0-250 day time category: 250-855: Adjusted Hazard Ratio (AHR)=1.11, p=0.69 (parox), AHR=1.48, p=0.26 (persist); 856-2200: AHR=1.24, p=0.40 (parox), AHR=2.16, p=0.04 (persist); and >2200: AHR=1.69, p=0.03 (parox), AHR=2.73, p<0.01 (persist). Among all patients, all-cause mortality increased as first ablation was delayed beyond 2.3 years after diagnosis (AHR 3.05, p = 0.047).

Conclusion:
In this registry analysis, delayed time to first ablation after diagnosis of both persistent and paroxysmal AF was associated with higher rates of atrial arrhythmia recurrence and all-cause mortality after 5 years.
Abstract 17325: Obesity, Blood Pressure, and Diurnal Variation in Natriuretic Peptides: A Clinical Trial
Authors: Parcha Vibhu , Patel Nirav , GUTIERREZ Orlando M , Li Peng , Musunuru Kiran , Margulies Kenneth B , Cappola Thomas P , Wang Thomas J , Arora Garima , Arora Pankaj
Published: May 2021

Background:
Obese individuals have disturbed blood pressure (BP) rhythmicity and relative natriuretic peptide (NP) deficiency. The relationship of diurnal variation in NP levels and 24h BP rhythm is not known. Furthermore, mechanisms behind difference in circulating NPs in healthy obese and lean individuals has not been explored. We conducted a prospective clinical trial to evaluate 1) the diurnal rhythmicity of NPs and its relationship with 24-hour BP rhythm between healthy lean and obese individuals, and 2) elucidate mechanism behind NP deficiency in obese.

Methods:
Healthy, normotensive, lean (BMI:18.5-25 kg/m
2
) and obese (BMI:30-45 kg/m
2
) individuals aged 18-40 years, underwent 24-hour standardized inpatient protocol involving ambulatory BP monitoring (ABPM), controlled light intensity, and 10 blood draws, following 5-days of standardized diet. NP gene expression was evaluated in a cohort of 37 healthy donor heart tissues obtained from the MAGNet repository.

Results:
Among 52 participants screened, a total of 40 participants (18 lean; 22 obese) were enrolled. Diurnal variation in MRproANP levels was seen in both lean and obese individuals (p for rhythmicity=0.001). The mesor of the NP rhythm was 15% (8.5-21.6%) lower in obese. The diurnal variation in MRproANP was in antiphase with diurnal variation of systolic BP (p<0.001) (
Figure
). Obese participants had lower 24h renin levels (p=0.06) and higher nocturnal sodium excretion (p=0.08). Among obese, there was lower expression of NP production genes (
NPPA, NPPB)
(p<0.05)
,
and higher expression of clearance gene (
NPR3
) (p<0.001) in heart tissue.

Conclusions:
In a mechanistic human trial, we elucidate key neurohormonal differences in rhythm and evidence of poor salt handling in obese. Decreased production and increased clearance may contribute to the NP deficiency in obese. Targeting the diurnal NP-BP rhythm axis may reduce the cardiovascular risk burden, specifically in obese individuals.
Abstract 17346: Loss of Neuropilin 2 Impairs Lymphangiogenesis and Exacerbates Lymphedema
Authors: Gao Yao , LEE Yang , Almazyad Asma , Birsner Amy , Li David , Wong Scott , Wen Aiyun , D'Amato Robert , adam Rosalyn , Srinivasan Sathish , Chen Hong , Bielenberg Diane
Published: May 2021

Dysfunctional lymphatic networks can lead to lymphatic diseases such as lymphedema as well as aggravate cardiovascular diseases such as atherosclerosis and hypertension. Some primary lymphedema patients have mutations in the
Neuropilin 2
(
NRP2
) gene, which encodes a transmembrane receptor that acts with VEGFR3 for the ligands VEGF-C and VEGF-D. Nrp2 has been shown to be a key regulator of lymphatic vessel development in the neonate as global
Nrp2
-deficient mice suffer from reduced lymphatic density. However, Nrp2 protein expression is dramatically downregulated after birth and its role in adult lymphangiogenesis or its relevance in lymphedema is less clear. Our hypothesis is that Nrp2 expression is necessary for optimal lymphangiogenesis and proper lymphatic drainage function in the adult, and that loss of
Nrp2
, either genetically or transcriptionally via down-regulation by specific transcription factors, may worsen lymphedema. In acute and chronic mouse inflammation models, we found that loss of
Nrp2
specifically in the lymphatic endothelium (

prox1-cre
ERT2
;Nrp2
f/f

) resulted in prolonged swelling and reduced lymphatic drainage compared to control mice. Using the VEGFC-induced corneal lymphangiogenesis model and the tail wound-induced secondary lymphedema model, LEC-Nrp2-iKO mice showed diminished lymphangiogenesis and reduced lymphatic drainage compared to littermate controls. Furthermore, primary mouse dermal LEC isolated from Nrp2-iKO mice reveal suppressed VEGFR3 activation, signaling, and proliferation following VEGF-C stimulation, compared to LEC isolated from control mice. Collectively, our results identify Nrp2 as a critical mediator of lymphangiogenesis and homeostatic lymphatic drainage function in adult tissues.
Abstract 17352: Seasonal Trends of Acute Idiopathic Pericardial Effusion Requiring Pericardial Drainage
Authors: Furqan Muhammad M , Yesilyaprak Abdullah , Verma Beni R , Lak Hassan Mehmood , Gangadharamurthy Dakshin , Hussain Muzna , Collier Patrick H , Klein Allan L
Published: May 2021

Background:
The seasonal trends of idiopathic pericardial effusion (PEff) are not known. Small PEff is usually asymptomatic but moderate to large PEff may lead to cardiac tamponade necessitating pericardial drainage procedures. Seasonal variations of PEff can help identify the association with viral infections that follow a seasonal pattern. Therefore, we sought to characterize the seasonal trends of moderate to large PEff.

Methods:
We retrospectively identified pericardial effusion patients from January 2015 to December 2019. Moderate to large PEff was defined as PEff requiring either pericardiocentesis or pericardial window. Patients with minimal to small PEff, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis), cardiac surgeries/invasive procedures, hemopericardium, chronic pericarditis, malignancy, and metastasis were excluded. Data was acquired from electronic medical records and frequencies, means, percentages, and chi-square test statistics were calculated.

Results:
Of the 472 patients with PEff, 63% (n=296) were males and 37% (n=176) females. The median age was 61 years. Pericardiocentesis was performed in 65% of patients and 35% had pericardial window. All seasons had similar incidence of PEff (winter 27%, spring 25%, summer 24%, fall 23%, [X
2
=1.81, p=0.612]). The incidence also remained same across all the quarters of the year (Q1 25%, Q2 25%, Q3 26%, Q4 24%, [X2=0.119, p=0.990). The incidence of pericardiocentesis and pericardial window in winter (27% vs 27.5), Spring (22% vs 31%), summer (26% vs 20%), fall (25% vs 20%) showed no difference (X2=6.40, p=0.094).

Conclusion:
The incidence of moderate to large acute idiopathic pericardial effusion is consistent across all seasons and quarters. Similarly, no significant seasonality was associated with pericardiocentesis and pericardial window procedures.
Abstract 17357: Direct Cardiac Reprogramming Using Combinatorial Modified mRNA
Authors: Kaur Keerat , Mahmoud Asharee , Girard Hanna , Kurian Ann Anu , Zak Magdalena , Chepurko Elena , Eliyahu Efrat , Hajjar Roger , Rafii Shahin , Zangi Lior
Published: May 2021

Introduction:
Despite various clinical modalities, ischemic heart disease remains among the leading causes of mortality and morbidity worldwide. The elemental problem is the immense loss of cardiomyocytes (CMs) post-myocardial infarction (MI). Reprogramming non- cardiomyocytes (non-CMs) into cardiomyocyte (CM)-like cells in vivo is a promising strategy for cardiac regeneration: however, the traditional viral delivery method hampered its application into clinical settings due to low and erratic transduction efficiency.

Methods:
We used a modified mRNA (modRNA) gene delivery platform to deliver different stoichiometry of cardiac-reprogramming genes (Gata4, Mef2c, Tbx5 and Hand2) together with reprogramming helper genes (Dominant Negative (DN)-TGFβ, DN- Wnt8a and Acid ceramidase (AC)), named 7G, to induce direct cardiac reprogramming post myocardial infarction (MI).

Results:
Here, we identified 7G modRNA cocktail as an important regulator ofthe cardiac reprogramming. Cardiac transfection with 7G modRNA doubled cardiac reprogramming efficiency (57%) in comparison to Gata4, Mef2C and Tbx5 (GMT) alone (28%)
in vitro
. By inducing MI in our lineage tracing model, we showed that one-time delivery of the 7G-modRNA cocktail reprogrammed ~25% of the non-CMs in the scar area to CM- like cells. Furthermore, 7G modRNA treated mice showed significantly improved cardiac function, longer survival, reduced scar size and greater capillary density than control mice 28 days post-MI. We attributed the improvement in heart function post modRNA delivery of 7G or 7G with increased Hand2 ratio (7G-GMT Hx2) to significant upregulation of 15 key angiogenic factors without any signs of angioma or edema.

Conclusions:
7G or 7G GMT HX2 modRNA cocktails boosts
de novo
CM-like cells and promotes cardiovascular regeneration post-MI. Thus, we highlight that this gene delivery approach not only has high efficiency but also high margin of safety for translation to clinics.
Abstract 17369: Addressing Missed Opportunities for Cardiometabolic Primary Prevention of Veterans Referred for Stress Testing
Authors: Johnson Ysanne , Mattei Sheila M , Burg Matthew , Meadows Judith L
Published: May 2021

Introduction:
Patients presenting to stress testing have a high prevalence of cardiometabolic risk factors (RF) which are not at guideline supported goals. Referral to stress testing is often a patient’s first presentation to CV care and represents a missed opportunity for delivery of risk reduction strategies.

Hypothesis:
Implementation of a cardiometabolic prevention initiative for cardiology-naïve patients referred to stress testing will result in improved delivery of guideline-directed prevention care.

Methods:
A consecutive prospective cohort of patients who underwent stress testing (12/1/2019-1/31/2020) after implementation of a linked cardiometabolic prevention referral for those with low risk stress tests was compared to a retrospective standard of care (SOC) cohort (9/1/2019-10/1/2019) from a single center Veterans Hospital. Outcomes assessed were change in CV risk reduction care at 90 days following stress test.

Results:
Of 181 patients, 62.5% were naïve to cardiology specialty care, had >1 CV risk factor not meeting guideline goals, 6% had typical angina as presenting symptoms, and greater than 70% of stress tests were normal or low risk. Baseline CV RF were common and failed to reach goals in SOC and intervention cohorts respectively with LDL above goal (40 vs. 33%), stage 1 or greater hypertension (67 vs 81%), Diabetes with HgA1c > 7 (48 vs. 21%), overweight or obese (68 vs. 79%), current tobacco (11 vs. 12%), and elevated mean 10-year ASCVD risk (32 vs.20%). At 90 days, 28% of SOC cohort had intensification of CV prevention care as compared to 76% of intervention cohort (X
2
26.8, p<0.05).

Conclusions:
A stress testing setting represents a valuable opportunity to deliver cardiometabolic prevention care. Integration of risk reduction strategies is imperative to shift from cardiac disease management to patient centered health promotion.
Abstract 17375: The Potential Role of Stress-Associated Neurobiological Metabolism in the Cardiovascular Sequelae of Sleep Apnea
Authors: Ghoneem Ahmed , Osborne Michael , Abohashem Shady , Zureigat Hadil , Dar Tawseef , Abbasi Taimur , Naddaf Nicki , Akuffo Emma , Tawakol Ahmed A
Published: May 2021

Introduction:
Obstructive and central sleep apnea (SA) induce sleep fragmentation and associates with HTN and cardiovascular diseases (CVDs). Sleep fragmentation is known to increase stress. Further, heightened stress-associated neurobiological metabolism (particularly amygdalar activity - AmygA), potentiates atherosclerosis. However, it is unknown: 1) whether SA increases AmygA in humans, or 2) whether AmygA mediates the link between SA and its CV consequences (HTN and CVD).

Hypothesis:
SA associates with higher AmygA which in turn associates with hypertension (HTN) and myocardial infarction (MI).

Methods:
We studied a cohort of 36424 participants within the Partners Biobank. Diagnoses of MI and sleep apnea and relevant clinical data were obtained from International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes. A subset of 1520 patients provided clinically indicated 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. AmygA was measured using validated measures.

Results:
Of 36424 participants, 6596 (18.1%) had SA, 20881(57.3%) had HTN and 4033 (11.1%) had MI. OSA significantly associated with HTN (OR [95%CI]: 3.2 [2.95, 4.48], p<0.0001) and MI (1.30 [1.21, 1.41], p<0.001) in multivariable models. SA associated with AmygA (β [95%CI]: 0.183 [0.058, 0.337], p=0.006). AmygA associated with HTN (1.18 [1.02, 1.38], p= 0.028). Further, AmygA associated with MI (1.28 [1.11, 1.46], p=0.0005). Moreover, AmygA mediated the association between SA and HTN and between SA and MI (p<0.05 for both, figs 1a and 1b).

Conclusion:
Our findings suggest that SA increases the risk of HTN & MI via a mechanism that involves heightened amygdalar activity. This potential mechanism may inform novel treatments.
Abstract 17402: Single Nuclei RNA-sequencing of Human Hypertrophic Cardiomyopathy Myectomy Samples Reveals Common Novel Mechanisms of Pathogenesis and Potential Therapeutic Targets Regardless of Genotype
Authors: Larson Amy , Rastegar Hassan , Huggins Gordon S , Rowin Ethan J , Maron Martin S , Maron Barry J , Chin Michael T
Published: May 2021

Introduction:
Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease, often resulting in left ventricular outflow tract obstruction, relieved by surgical myectomy. Current treatments are largely palliative and do not target the root causes. Understanding the molecular drivers of the disease could lead to alternative treatment strategies through identification of novel therapeutic targets.

Methods:
We performed single nuclei RNA-sequencing (snRNA-seq) on thousands of nuclei from 9 patient myectomy samples and septal tissue from 4 unused donor hearts selected randomly without regard to genotype to identify the cell populations and determine the gene expression patterns in individual cells. Each sample was processed individually using Seurat v3 for quality control and normalization. Next, all 13 samples were integrated into a combined dataset for clustering and differential gene expression analysis to identify markers specific to each cluster and to assign cell identities.

Results:
Our results revealed several clusters of cardiomyocytes with differences in sarcomeric and metabolic gene expression. Several fibroblast populations were also observed. Numerous genes were differentially expressed between the HCM and normal samples. For example,
RARRES1
expression was observed in many of the fibroblast populations in the normal samples, but was absent in the HCM samples.
RARRES1
is involved in regulating fatty acid metabolism and autophagy, both of which are altered in HCM. Additionally, expression of
PLA2G2A
was absent in the HCM samples but was present in almost every cell type in the normal controls.
PLA2G2A
is involved in suppression of RTK mediated hypertrophic signaling, impacts lipid signaling, and has tumor suppressor properties. Thus, both
RARRES1
and
PLA2G2A
may represent novel targets in HCM.

Conclusions:
This approach reveals novel potential therapeutic targets within common final HCM pathological pathways independent of genotype that have the potential to guide development of alternative treatment strategies. Further analysis of larger datasets using this approach will likely identify even more common pathway targets and identify additional common mechanisms in the pathogenesis of obstructive HCM.
Abstract 17432: We Are Baffled: An Unusual Presentation of STEMI
Authors: Soofi Muhammad , Garg Swapnil , Sadhu Srikanth
Published: May 2021

Background:
Adult congenital heart disease is most commonly complicated by arrhythmias and very rarely by acute coronary syndromes. We present a rare case of ST elevation myocardial infarction (STEMI) in a young 35-year-old patient with congenital transposition of great vessels.

Case Presentation:
A 35-year-old female with a past medical history of transposition of the great vessels (d-TGA) status post arterial baffle operation in infancy, with prior atrial arrhythmias and severe RV failure, presented to our facility with crushing substernal chest pain radiating down her left arm. ECG was significant for ST elevation in the inferior leads and high sensitivity troponin was elevated. She was taking Rivaroxaban. She was taken emergently to the catheterization lab where she was found to have 100% occlusion of the apical left anterior descending artery secondary to an embolus with no angiographic disease in any other epicardial vessel. Transthoracic echocardiography showed severe dilation of the right ventricle with severe tricuspid regurgitation. The embolic lesion was deemed not amenable to percutaneous intervention and the patient was treated conservatively with a heparin drip. The embolus was presumed to originate from the hyper-trabeculated and distended right ventricle in spite of chronic rivaroxaban therapy and she was started on warfarin. Presently she is stable, awaiting a heart transplant.

Discussion:
Extensive literature review revealed four reported cases of acute coronary syndrome secondary to emboli in patients with surgically corrected TGA. Patients with d-TGA are most often surgically corrected with an arterial switch procedure. But in Baffle procedures (Mustard or Senning) such as the one in this patient, the right ventricle becomes the systemic ventricle. The most common complications as an adult are right ventricular dilation, severe tricuspid regurgitation and atrial arrhythmias, all three of which were noted in our patient.

Conclusion:
Our patient developed all three of the most common adult complications of surgically corrected d-TGA, ultimately resulting in the rare and extreme manifestation of an embolic STEMI.