bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10499: The Heart Failure-Induced Long Non-Coding RNA Heat4 Reduces the Inflammatory Response of Non-Classical Monocytes and Mediates Regeneration After Vascular Injury
Authors: Kneuer Jasmin M , Meinecke Tim , Moebius-Winkler Maximilian Nicolas , Weiss Ronald , Haas Jan , Garfias-Veitl Tania , von Haehling Stephan , Keller Till , Thiele Holger , Lurz Philipp , Speer Timo , Laufs Ulrich , Boeckel Jes-Niels
Published: March 2022

Background and Purpose:
Activation of the immune system correlates with the severity and the prognosis of patients with heart failure (HF). This study aims to identify and characterize long non-coding RNAs (lncRNAs) as a potential mechanistic link between the pathophysiology of HF and the activation of the immune system.

Methods and Results:
Using next-generation sequencing, we identified the lncRNA Heat4 to be 2-fold upregulated in the blood of patients with HF compared to controls (N=4; p<0.05). Heat4 induction was validated in an independent second patient cohort via qPCR (HF: N=63; Controls: N=38; p<0.05). Magnetic-activated cell sorting revealed non-classical monocytes as the primary cellular source of Heat4 (N=4; 3.37-fold compared to classical monocytes; p<0.05). This finding was verified by single-cell RNA sequencing. Overexpression of Heat4 in monocytes decreased inflammation, as indicated by a reduction of Interleukin 1β (IL1β) expression (N=6; 38.71% reduction). Accordingly, reduction of Heat4 caused upregulation of IL1β levels (N=5; 1.51-fold; p<0.05).
In vivo
, overexpression of Heat4 in human monocytes increased vascular regeneration after injury of the carotid artery in NOD-SCID mice (N=6; 1.85-fold compared to injection of control monocytes; p<0.05).

Conclusion:
The long non-coding RNA Heat4 is elevated in the blood of HF patients. Mechanistically, Heat4 limits the extent of the inflammatory response of non-classical monocytes and leads to a faster regeneration after vascular injury. Therefore, lncRNAs such as Heat4 may provide novel targets for future heart failure treatments.
Abstract 10515: Deep Phenotyping of Heart Failure with Machine Learning: An Echocardiographic Community Study
Authors: Larson Nicholas B , Weston Susan , Michelena Hector I , Bielinski Suzette J , Jiang Ruoxiang , Joo Jungnam , Manemann Sheila M , Chamberlain Alanna M , Roger Veronique L
Published: March 2022

Introduction:
Heart failure (HF) is a clinical syndrome with high mortality. Left ventricular ejection fraction (EF) determines clinical phenotyping and HF is classified most often as preserved (HFpEF) or reduced (HFrEF) EF. The importance of expanding phenotyping beyond EF is recognized. We hypothesized that machine learning applied to echocardiography will provide information important for deep phenotyping.

Methods:
We collected clinical and echo data in a HF community cohort between 2013 and 2017. Unsupervised clustering was applied to 23 echo variables using partitioning around medoids (PAM), with Gower dissimilarity used to address the mixed variable types. Proportional hazards regression examined the association between cluster assignment and death.

Results:
We identified 4978 persons with HF [mean age 73.9 years (SD 13.9), 47% women] with echocardiography within 6 months of diagnosis. We identified 2 primary clusters using echo variables, as depicted using t-Distributed Stochastic Neighbor Embedding (t-SNE) applied to the dissimilarity matrix (Figure). Diastolic function variables exhibited the largest differences by clusters as shown by absolute standardized differences (Table). After 3.2
+
1.9 years of follow up, 2001 deaths occurred. Assignment to cluster 2 was associated with a near 20% excess risk of death independent of age, sex, comorbidity, and EF [HR 1.17 (1.07, 1.28) p<0.001].

Conclusions:
Unsupervised clustering applied to echocardiography in a large community HF cohort identified 2 distinct clusters, which defined HF subgroups with different characteristics and were independently associated with risk of death.
Abstract 10523: Prevalence and Characteristics of Aortic Dissection in Out-of-Hospital Cardiac Arrest Patients with Pulseless Electrical Activity as an Initial Rhythm
Authors: Kaichi Ryota , Marume Kyohei , Mikami Takafumi , Ikebe Sou , Takae Masafumi , Mori Takayuki , Komaki Soichi , Toida Reiko , Kurogi Kazumasa , Nagamine Yasuhiro , Matsuyama Masakazu , Yamaguchi Tetsuro , Yano Takao , Tsujita Kenichi , Yamamoto Nobuyasu
Published: March 2022

Introduction:
The utility of extracorporeal cardiopulmonary resuscitation (ECPR) for patients with pulseless electrical activity (PEA) is still unclear and the appropriate patient selection is necessary. We evaluated the characteristics of patients with aortic dissection (AD), which is a major contraindication for ECPR, among patients with PEA using a city-wide (population=120.000) prospective registry of patients who experience out-of-hospital cardiac arrest (OHCA) whom cause of death are assessed by post-mortem computed tomography (PMCT).

Methods and Results:
1373 patients who experienced OHCA between 2008 and 2020, and 1,235 (90%) were assessed their cause of death by CT in the city. 359 patients with PEA as an initial rhythm were finally included to this study and 44 had AD (12%). Female (OR, 2.37; 95% confidence interval [CI], 1.25-4.52; P=0.008), sudden onset (OHCA within 60 min from the onset of new symptoms) (OR, 2.61; 95% CI, 1.20-5.70; P=0.015), and the prevalence of hypertension (OR, 3.16; 95% CI, 1.45-6.88; P=0.004) were independently associated with the presence of AD. Based on the number of these 3 factors, the risk of AD was stratified into 0% (score 0), 12% (score 1 or 2) and 34% (score 3). Furthermore, among patients underwent post-resuscitation electrocardiogram (n=166), inferior segment ST depression was significantly associated with AD (OR, 3.89; 95% CI, 1.17-12.9; P=0.027) and its absence allowed us to identify low risk (4%) group in patients with score 1 or 2 (Figure).

Conclusions:
The risk of AD for OHCAs with PEA was 12%, but stratification based on interview and electrocardiography allowed us to identify lower risk groups (0% or 4%).
Abstract 10526: Surface Located Adiponectin On Adipocytes-derived Exosomes Mediates Adipocytes/cardiomyocytes Communication And Contributes To Cardioprotection
Authors: Zhang Zhen , Zhu Di , Meng Zhijun , Zhao Jianli , Yao Peng , tsukuda jumpei , Koa Jonathan , Liu Demin , Gan Lu , LAU Wayne Bond , Xie Dina , Lopez Bernard L , Christopher Theodore , Gao Erhe , Koch Walter J , Ma Xinliang , Wang Yajing
Published: March 2022

Introduction and Hypothesis:
Increasing evidence emphasizes the roles of adipocyte-cardiomyocyte (ADp-CM) communication plays in health and diabetes. We recently reported that diabetes switched ADp-derived Exosomes (ADp-Exo) from carrying cardioprotective molecules to delivering cardiotoxic molecules to CM. However, the molecular mechanisms mediating ADp-Exo cardioprotection and its alteration by diabetes remain unknown.

Methods and Results:
ADp-Exo was isolated from epididymal white adipocytes of WT mice. Western Blot demonstrated high level of adiponectin (APN), a potent cardioprotective adipokine, present in ADp-Exo. More interestingly, APN was detected on the surface of ADp-Exo by flow cytometry using Exo-flow kit (System Biosciences). To determine whether surface-located APN on ADp-Exo protect heart, WT ADp-Exo were intramyocardially injected. Mice were subjected to 90 minutes coronary occlusion, followed by 4 weeks of reperfusion. Cardiac function was evaluated by echocardiograph weekly. WT ADp-Exo significantly reduced MI/R injury
in vivo
, as evidenced by improved LVEF, radial and longitudinal myocardial Strain and SR (vs vehicle group, p<0.05). Importantly, pre-incubation of ADp-Exo with an APN neutralization antibody blocked ADp-Exo cardioprotection. To determine the role of CM AdipoR1,
ex vivo
and
in vitro
experiments were performed. WT ADp-Exo activated AdipoR1 pathway (increased phosphorylation of ACC, ERK and AMPK) in CM and protected against cell injury and death (MTT and LDH assay). However, surface APN blocked WT ADp-Exo or APN
-/-
ADp-Exo failed to active this signaling and protection. WT ADp-Exo failed to activate cell salvage kinases in AdipoR1
-/-
CM. Finally, overexpression of GRK2, a pathogenic molecule that we reported to cause AdipoR1
S205
phosphorylation, blocked WT ADp-Exo cardioprotection. AAV9-mediated overexpression of a phosphorylation resistant AdipoR1 (AdipoR1
S205A
) restored ADp-Exo protective action.

Conclusions:
We demonstrate for the first time that ADp-Exo surface located APN mediates ADp-CM communication via CM AdipoR1 pathway, promoting cardioprotection. This protective system is blocked by GRK2-induced AdipoR1 phosphorylation in diabetic heart, promoting MI/R injury.
Abstract 10537: Clinical, Sociodemographic and Neighborhood Characteristics and Adverse Pregnancy Outcomes
Authors: Gaballa Dianna , Pachtman Sarah L , Blitz Matthew J , Fishbein Joanna S , Hentz Roland , Vaidean Georgeta , Grayver Evelina , Weinberg Catherine , Gianos Eugenia
Published: March 2022

Introduction:
Adverse pregnancy outcomes (APOs) are risk enhancing factors for future cardiovascular (CV) disease. Our study aims to understand the clinical, sociodemographic and neighborhood factors of patients who suffered APOs in our health system.

Methods:
We performed a retrospective analysis of 66,136 single-gestation pregnancies from 7 hospitals in the Northwell Health System between March 2018 and June 2020. Pregnancies with known APO status were included in final analysis (n=64,804). Data extracted from EHR included demographics, parity, insurance, hospital of delivery, medical history, and APO outcomes: pre-term birth (PTB), stillbirth (SB), small for gestational age (SGA) and low birth weight (LBW). Median neighborhood household income, percent unemployed, and household size (extracted from census data based on zip code) were used to represent the mean demographics of those living within certain geographic regions.

Results:
In our study population, the average ±SD age was 31.4 ±5.4 years; 46.9% were white, 12.4% were black, 12.4% were Asian and 52.3% were overweight or obese. The composite incidence of SB, SGA and LBW was 13.8% while incidence of PTB was 7.2%. Being single or having public health insurance had an increased odds of overall APOs, OR 1.4 (95%CI 1.3-1.4) and OR 1.3 (95%CI 1.2-1.3), respectively. Median neighborhood household income was significantly associated with odds of APOs, with lower income categories having increased odds of APOs and odds of PTB compared to higher income categories. Those with a hypertensive disorder (HTN) (during or pre-pregnancy) had increased odds of having an APO compared to those without, OR 2.2 (95%CI 2.1-2.4). Those with HTN, glucose intolerance or obesity (pre-pregnancy BMI ≥ 40) during or pre-pregnancy had increased odds of a PTB compared to those without any of these conditions, OR 3.6 (95%CI 3.4 - 3.9), OR 1.7(95%CI 1.6-1.9) and OR 1.9 (95%CI 1.7-2.2), respectively.

Conclusions:
CV risk factors, sociodemographic and neighborhood characteristics are likely associated with APOs. These potential relationships may provide useful information for CV prevention in pregnancy. Future research is needed to further elucidate these associations.
Abstract 10546: Predictors of Changes in Peak Oxygen Consumption Following Outpatient Cardiac Rehabilitation: Importance of Cardiac Rehabilitation Adherence
Authors: Little Kasara A , Smith Joshua R , Medina-inojosa Jose , Chacin Suarez Audry , Taylor Jenna L , Hammer Shane , Fischer Karen , Bonikowske Amanda , Squires Ray W , Thomas Randal J , Olson Thomas P
Published: March 2022

Introduction:
Cardiac rehabilitation (CR) is associated with improvements in exercise capacity (peak oxygen uptake (VO
2
peak)); however, 23% of CR patients do not improve VO
2
peak following CR. CR adherence (i.e. number of CR sessions attended) has been proposed to play an important role in VO
2
peak improvement following CR, but has not been investigated. Identifying clinical predictors of VO
2
peak improvement are critical as the degree of VO
2
peak improvement is associated with improved long-term outcomes in these patients.

Purpose:
To determine if clinical characteristics and number of CR sessions attended were predictive of patients who exhibited improvement in VO
2
peak following CR.

Methods:
Using the Rochester Epidemiology Project records-linkage system, we identified all consecutive patients >18 years old from Olmsted County, Minnesota who underwent cardiopulmonary exercise testing prior to and following CR from 1999 to 2017. Regression models were created to assess clinical predictors of VO
2
peak improvement (>0% baseline) following CR.

Results:
The analysis included 804 patients (75% men) with a mean age of 60.7±12.4 years. Of the 804 patients, 609 (76%) patients exhibited VO
2
peak improvement following CR. Significant univariate predictors of VO
2
peak improvement included younger age (OR: 0.99, 95% CI: 0.97-1.00), lower pre-CR VO
2
peak (OR: 0.97, 95% CI: 0.94-0.99), history of peripheral artery disease (OR: 0.48, 95% CI: 0.32-0.73), and smoking (OR: 0.63, 95% CI: 0.45-0.90). Significant independent predictors of VO
2
peak improvement from a multivariate analysis included younger age (OR: 0.98, 95% CI: 0.96-1.00), number of CR sessions (OR: 1.02, 95% CI: 1.01-1.03), lower pre-CR VO
2
peak (OR: 0.94, 95% CI: 0.91-0.96), history of peripheral artery disease (OR: 0.42, 95% CI: 0.27-0.66), and smoking (OR: 0.56, 95% CI: 0.39-0.82).

Conclusions:
These findings demonstrate the importance of CR adherence and individual clinical characteristics in influencing VO
2
peak improvement following CR in patients with CVD. These findings may influence the clinical practice by providing specific clinical characteristics to account for when personalizing the CR treatment plan to maximize positive outcomes.
Abstract 10558: Characteristics and Prognosis of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis with Cardiac Involvement
Authors: Liu Huazhen , Huang Yongfa , Guo Xiaoxiao
Published: March 2022

Introduction:
Cardiac involvement (CI) is relatively common in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV), including granulomatosis with polyangiitis/microscopic polyangiitis (GPA/MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The characteristics of AAV-CI require further investigation.

Hypothesis:
The cardiac manifestations and prognosis differ between GPA/MPA-CI and EGPA-CI.

Methods:
AAV-CI patients admitted to our hospital from Jan 1998 to Dec 2020 were retrospectively recruited. Prognosis was analyzed with log-rank test and multivariable Cox regression.

Results:
A total of 71 AAV-CI patients, including 37 (52.1%) females and 32 (45.1%) EGPA patients, were enrolled and EGPA-CI patients were significantly younger (49 [34-61] vs 64 [55-76] years,
P
< 0.01). CI presented as cardiomyopathy (63.4%), arrhythmia (28.2%), and acute coronary syndrome (22.5%). EGPA-CI patients were less complicated with atrial fibrillation (
P
< 0.01), and more with pericardial effusion (
P
= 0.04) and cardiomyopathy (
P
= 0.02). Intraventricular thrombosis was more common in EGPA-CI, but the difference was not significant (1, 2.7% vs 5, 15.6%,
P
= 0.09). During a median follow-up of 19 months, 24 (33.8%) patients died. The survival rate of our cohort was 75.7% at 1 year, and EGPA-CI patients survived GPA/MPA-CI patients (82.0% vs 70.5% at 1 year,
P
= 0.02). The independent prognostic factors for GPA/MPA-CI included peak NT-proBNP > 12870 pg/ml (HR 5.1 [95%CI 1.6-16.2],
P
< 0.01), peak CRP > 74.5 mg/L (4.4 [1.2-15.9],
P
= 0.03), and functional tricuspid regurgitation (26.0 [2.7-248.4],
P
< 0.01), while gastrointestinal involvement (8.9 [1.6-49.1],
P
= 0.01) was identified as the sole independent prognostic factor for EGPA-CI.

Conclusions:
Cardiomyopathy, pericardial effusion and intraventricular thrombosis were more frequent in EGPA-CI than in GPA/MPA-CI. EGPA-CI had better prognosis than GPA/MPA-CI with different predictors.
Abstract 10561: Attending Cardiac Rehabilitation Reduces Incidence of Dementia but Not Mild Cognitive Impairment in Patients with Coronary Artery Disease
Authors: Taylor Jenna L , Medina-inojosa Jose R , Petersen Ronald C , Graff-Radford Jonathan , Johnson Bruce D , Bonikowske Amanda R
Published: March 2022

Introduction:
Coronary artery disease (CAD) has been associated with cognitive decline. Cardiac rehabilitation (CR) is a class 1A recommendation for patients with CAD as it reduces future cardiac events and mortality. However, the impact of CR on incidence of mild cognitive impairment (MCI) and dementia has not been extensively studied. We investigated the association of CAD on incidence of MCI and dementia; and whether CR attendance reduces incidence of MCI and dementia in patients with CAD

Methods:
The Mayo Clinic Study of Aging (MCSA), a prospective, population-based cohort was probed for this study. At baseline and every 15-months thereafter, subjects were evaluated for MCI and dementia using a standardized protocol. Data on CR participation were collected via record linkage to the Rochester Epidemiology Project. To evaluate association with incident MCI or dementia, cox proportional hazard models were used and adjusted for age, sex, and clinical predictors of cognitive decline. Participants with MCI at baseline were excluded for MCI analysis and adjusted for in dementia analysis.

Results:
We included 5960 MCSA participants (female: 50%; age: 70±13). Of those, 1934 participants (32%) had CAD and 702 (12%) had MCI at baseline. Mean follow-up was 3.9±3.7yrs, with 760 incident cases of MCI (13%) and 290 cases of dementia (5%). CAD was a significant predictor of MCI and dementia, although after adjustment for other clinical predictors, CAD was only associated with MCI incidence (
Table 1, Figure
). Incidence of dementia was reduced in CAD patients who had a greater attendance at CR when adjusted for other predictors of cognitive decline (
Table 2
). Attendance at CR did not reduce incidence of MCI (
Table 2
).

Conclusions:
CAD was a significant predictor of MCI and dementia. In patients with CAD, a higher attendance of CR was associated with reduced incidence of dementia but not MCI. Specific CR programming and outcome targets may be needed to prevent MCI in patients with CAD.
Abstract 10564: Inverse Association Between Serum Albumin Levels and Myocardial Extracellular Volume in Patients with Severe Aortic Stenosis
Authors: Shiyovich Arthur , Plakht Ygal , Hammer Yoav , Aviv Yaron , Wiessman Maya , Shafir Gideon , Vaknin-Assa Hanna , Kornowski Ran , Hamdan Ashraf
Published: March 2022

Introduction:
Severe aortic stenosis (AS) is often characterized by myocardial interstitial fibrosis (MIF). MIF, classically measured by magnetic resonance imaging, was shown to be accurately measured by computed tomography (CT)-derived extra cellular volume fraction (ECVF). Serum albumin level (SA, g/dL) has been shown to correlate with ECVF among patients with heart failure preserved ejection fraction.

Aim:
To evaluate the association between SA and ECVF among patients with severe symptomatic AS.

Methods:
Patients with symptomatic severe AS who were evaluated as candidates for intervention between 2016 and 2018, were enrolled prospectively. All patients underwent pre- and post-contrast CT for estimating myocardial ECVF. Valid ambulatory SA within 6 weeks of the cardiac CT were obtained and classified as (tertials): <3.8, (3.8-4.19), ≥4.2 g/dL. Patients with acute systemic illness at the time of the albumin test were exclude.

Results:
The study included 68 patients, mean age 80.94±6.5, 53% females. Patients with lower SA were more likely to have chronic renal failure, prior percutaneous coronary interventions (PCI) and a reduced functional class. The mean ECVF (%) in the study cohort was 40.96±11.6%, significantly higher among the patients in the lower SA level groups (50±11.6% vs. 38.2±7.3% vs. 32.8±8.6% in the <3.8 g/dL, 3.8-4.19 g/dL, ≥4.2 g/dL groups respectively, p for trend<0.001). A statistically significant inverse correlation (figure 1) was found between SA levels and ECVF (r=-0.7, p<0.001). Multivariable analysis showed significant independent association between low SA and ECVF.

Conclusions:
SA level is inversely associated with CT-derived ECVF in patients with severe AS. Additional studies are warranted to elucidate the pathophysiological mechanisms explaining the observed association and potential clinical implications
Abstract 10571: Phase 1 Single-Dose Study to Evaluate Apixaban in Pediatric Subjects at Risk for Venous or Arterial Thrombotic Disorder
Authors: Garonzik Samira M , Byon Wonkyung , Patel Yogesh , Elsrougy Amira , Marchisin David , Perera Vidya , Chen Weidong , He Bing , Murthy Bindu
Published: March 2022

Introduction:
Standard-of-care antithrombotics in pediatric subjects (peds) include unfractionated/LMW heparin, aspirin, and vitamin K antagonists. Apixaban, a direct factor Xa (FXa) inhibitor indicated for VTE treatment (tx) and prevention in adults, may be an effective and convenient oral tx option with an acceptable safety profile in peds.

Objectives:
To evaluate pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of apixaban in peds at risk for venous or arterial thrombotic disorder; to support dose selection for apixaban pediatric program trials.

Methods:
This phase 1 study (NCT01707394) enrolled peds aged < 18 years (y) at risk for venous/arterial thrombotic disorder into groups by age. Peds undergoing tx/procedures or with conditions that may affect bleeding risk or apixaban exposure were excluded. A single apixaban dose (based on BSA; targeted to achieve adult exposures with apixaban 2.5 mg) was administered: 0.1 mg sprinkle capsule for age < 28 days (d); 0.4 mg/mL solution for ages 28 d to < 18 y (dose range: 1.08-2.19 mg/m
2
). Endpoints included PK, safety, tolerability, and PD (anti-FXa activity). For PK/PD, 4-6 blood samples were collected ≤ 26 h after dosing. A population PK (PPK) model developed with data from adults and peds was used to evaluate PK. Apparent oral clearance (CL/F) included a fixed maturation function based on published data.

Results:
From Jan 2013 to Jun 2019, 49 peds aged 9 d to 16 y received an apixaban dose. All AEs (n = 15) resolved; most were mild/moderate; none were bleeding-related. SAEs (1 seizure; 1 limb venous thrombosis) were not tx-related. Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in ages 12 to < 18 y. Maturation affected CL/F most notably in ages < 9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations with no apparent age-related differences, comparable to adults.

Conclusions:
Single apixaban doses were generally safe and well tolerated in peds. Study data and PPK model supported dose selection for phase 2/3 multiple-dose pediatric trials.
Abstract 10572: Efficacy and Safety of Protamine After Catheter Ablation of Atrial Fibrillation: Systematic Review and Meta-Analysis
Authors: Shah Kuldeep , Shah Siddharth , Turagam Mohit , Bhardwaj Rahul , Contractor Tahmeed , Mandapati Ravi , Natale Andrea , Lakkireddy Dhanunjaya , Garg Jalaj
Published: March 2022

Introduction:
Perioperative anticoagulation management with uninterrupted or minimally interrupted anticoagulation during atrial fibrillation (AF) ablation is thought to be critical to minimize thromboembolic complications. Protamine is often administered to neutralize the effects of heparin and expedite vascular hemostasis post-procedure.

Hypothesis:
To determine the efficacy and safety of protamine to expedite vascular hemostasis and ambulation in patients undergoing AF ablation.

Methods:
Electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from the inception through June 7, 2021, were performed. The primary outcome was time to ambulate (minutes) and hemostasis (minutes). The secondary outcome was any vascular complications or minor hematoma or cerebrovascular accidents.

Results:
A total of 5 eligible studies consisting of 637 patients (Protamine group: 515 and no protamine group: 497) were included in the meta-analysis. There was a significant reduction in time to ambulation {mean difference (MD): -176.60, 95% CI -266.87 - -86.32; p< 0.01} and in time to hemostasis between the two groups (MD -13.72, 95% CI -22.01 - -5.44, p<0.01) in the protamine group. There were no differences in the rates of vascular complications (RR 0.46 95% CI 0.17-1.24 for any vascular complication; RR 0.43, 95% CI 0.16-1.2 for minor hematoma) or cerebrovascular accidents (RR 0.62, 95% CI 0.08 - 4.98) between the two groups.

Conclusions:
Protamine administration was associated with reduced time to ambulation (176 minutes reduction) and time to hemostasis (13 minutes reduction) without an increase in any adverse events.
Abstract 10575: The Effect of Empagliflozin on the Biomarker Growth Differentiation Factor 15 in Patients with Heart Failure and Reduced Ejection Fraction: A Post-Hoc Study of a Randomized, Double-Blind, and Placebo-Controlled Trial
Authors: Omar Massar , Jensen Jesper , Kistorp Caroline N , Højlund Kurt , Larsen Julie H , Andersen Camilla Fuchs F , Videbaek Lars , Tuxen Christian D , Poulsen Mikael Kjaer K , Gustafsson Finn , Kober Lars , Schou Morten , Moller Jacob
Published: March 2022

Introduction:
Growth differentiation factor 15 (GDF-15) is considered as a biomarker of inflammatory and myocardial tissue injury. However, metformin increases plasma GDF-15, and may be responsible for the metabolic benefits (e.g. weight loss, decrease in Hemoglobin A1c and systolic blood pressure, and improvement in insulin resistance) effects in type 2 diabetes (T2D). Recently, sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated increment in GDF-15 in a proteomic analysis in T2D patients.

Hypothesis:
To examine SGLT2i’s effect on GDF-15 in HFrEF patients.

Methods:
This multicenter, randomized, double-blind, placebo-controlled exploratory sub-study enrolled 190 stable HFrEF patients with an ejection fraction of 40% or below. Patients were randomized (1:1) to empagliflozin 10 mg once daily or matching placebo for 12 weeks. Outcome measures were changes from baseline in GDF-15, high sensitive C-reactive protein (hsCRP), and high sensitive troponin T (hsTNT) adjusted for age, sex, BMI, T2D.

Results:
Mean age was 64 (SD, 11) years; 85% male, 13% with T2D, mean ejection fraction 29 (SD, 8)). Empagliflozin significantly increased GDF-15 compared to placebo [Empagliflozin: baseline, median (interquartile range (IQR)) 1177 (899-1720) pg/mL, follow-up, 1394 (970-1942) pg/mL: Placebo: baseline 1299 (915-1849) pg/mL, follow-up, 1276 (879-1924) pg/mL, adjusted ratio of change (1.10 [95% confidence interval (CI), 1.04-1.17]: p=0.002). There was no significant change in hsCRP (1.13 [95%CI, 0.89-1.43]: p=0.31), nor in hsTNT (1.09 [95%CI, 0.98-1.20]: p=0.12) (Figure 1).

Conclusions:
Empagliflozin significantly increased GDF-15 in predominantly non-diabetic HFrEF patients regardless of HF etiology, without a concomitant increase in hsCRP, or hsTNT compared to placebo. These results might explain the link between empagliflozin and the metabolic benefits seen in this population.
Abstract 10579: Vascular Impairment by Trimethylamine N-Oxide (TMAO) Uptake and the First Description of a TMAO Transporter in Endothelial Cells
Authors: Rittig Sascha T , Gaal Lidia , Schubert Marie R , Kneuer Jasmin M , Kokot Karoline Elizabeth , Hauke Jana , Okun Juergen G , Laufs Ulrich , Boeckel Jes-Niels
Published: March 2022

Introduction:
Trimethylamine N-oxide (TMAO) derived from dietary sources has been linked to a higher risk of atherosclerotic disease. However, the underlying mechanisms are not fully understood. Impairment of endothelial cells (ECs) by chronic inflammation or metabolic cues can lead to a loss of EC phenotype and function towards a mesenchymal cell type, a process contributing to atherosclerosis termed endothelial-to-mesenchymal transition (EndMT). Here, we investigate the potential uptake of TMAO and its impact on endothelial inflammation and EndMT.

Methods & Results:
Using tandem mass spectrometry, we found ECs to take up TMAO in a time-dependent manner (0.5 nmol/mg within 30 min rising to 5.8 nmol/mg TMAO/total protein after 24 h). The induction of ICAM1 (+26.5-fold) and E-Selectin (+77.7-fold, both p<0.05) indicated an inflammatory activation of ECs after TMAO uptake. The prolonged treatment of ECs with TMAO for 3 days induced EndMT, as indicated by increase of the mesenchymal markers Calponin 1 (+11.9-fold) and SM22 (+8.6-fold) and by a concomitant downregulation of endothelial LYVE1 (-92%, all p<0.05). Functionally, the EC barrier function was significantly impaired after prolonged TMAO treatment leading to an increase in vascular permeability (+2.36-fold).

The multitude of known human solute carrier proteins were screened in ECs for identification of a potential TMAO transporter. Single-cell RNA-sequencing revealed the Endothelial TMAO Transporter 1 (ETT1) to be upregulated in inflammatory-activated ECs of the myocardium. Overexpression of ETT1 resulted in a 61.7% higher intracellular TMAO concentration in ECs after 30 min of treatment. Downregulation of ETT1 by siRNA prevented TMAO-induced inflammation (-112% induction of E-Selectin and -105% induction of ICAM1) and EndMT (-315% induction of SM22 and -533% induction of Calponin 1) and restored EC barrier function (-78% induction of permeability).

Conclusions:
In summary, our study identifies that TMAO uptake into human ECs causes increased inflammation and induces EndMT. The TMAO-mediated impairment of EC function is prevented by down-regulation of the newly identified TMAO transporter ETT1. Our findings may help to better understand the interaction of diet and atherosclerosis.
Abstract 10580: Health Care Utilization After First-Line Cryoablation for Atrial Fibrillation
Authors: Zucchelli Giulio , Chun Julian K , Khelae Surinder Kaur , Földesi Csaba , Kueffer Fred , van Bragt Kelly , Scazzuso Fernando , On Young-Keun , Al-Kandari Fawzia , Okumura Ken ,   on behalf of the Cryo AF Global Registry Investigators
Published: March 2022

Background:
Cryoablation is superior to antiarrhythmic drugs (AAD) for the prevention of arrhythmia recurrence in drug naïve (first-line) patients with paroxysmal atrial fibrillation (AF). The adoption and outcomes of first-line cryoablation in a real-world setting are unknown.

Purpose:
To describe global usage, safety, efficacy, and healthcare utilization outcomes in patients treated with cryoablation for first-line management of AF.

Methods:
Cryo Global Registry (NCT02752737) is an ongoing, prospective, multicenter registry. AF patients with an index cryoballoon ablation performed according to local standards of care at 58 centers in 26 global countries were included. Subjects undergoing first-line cryoablation were compared to patients with prior failed AAD usage and/or taking AADs at baseline. Serious procedure-related complication rates, 12-month freedom from a ≥30sec AF/atrial flutter (AFL)/atrial tachycardia (AT) recurrence after a 90-day blanking period, and healthcare utilization were compared.

Results:
Of 1,394 total patients, 433 (31.1%) were treated with first-line cryoablation. The proportion of first-line enrollments varied widely by world region and country. AAD-refractory patients failed a mean of 1.2 ± 0.5 AADs prior to cryoablation. Freedom from AF/AFL/AT after cryoablation in first-line and AAD-refractory was 90.0% (95% CI: 86.4-92.7%) vs 84.4% (95% CI: 81.5-86.8%) in paroxysmal AF and 72.9% (95% CI: 58.6-83.0%) vs 70.2% (95% CI: 62.9-76.4%) in persistent AF (overall p=0.02), respectively. Serious adverse event rates were not statistically different between first-line and AAD-refractory patients (2.3% vs 3.4%; p=0.32), with highest rates being groin-site complications (0.7% vs 0.5%), respectively. Freedom from repeat ablations in first-line vs AAD-refractory was 95.5% (95% CI: 92.7 - 97.2%) vs 93.1% (95% CI: 91.0 - 94.7%) in paroxysmal AF and 84.7% (95% CI: 71.8 - 92.1%) vs 88.2% (95% CI: 82.5 - 92.2%) in persistent AF (overall p=0.35), respectively.

Conclusion:
The current data support cryoablation as an early intervention strategy for treatment of patients with AF.
Abstract 10583: A Novel Functional Variant, P.Gln419Pro, Residing Outside the
SCN5A
-Encoded Na
V
1.5 Voltage-Sensing Domain Causes Multifocal Ectopic Purkinje-Related Premature Contractions
Authors: Gao Xiaozhi , Ye Dan , Zhou Wei , Tester David J , Ackerman Michael J , Giudicessi John
Published: March 2022

Background:
Multifocal ectopic Purkinje-related premature contractions (MEPPC), the most recent addition to the spectrum of
SCN5A
-mediated cardiac channelopathies, is characterized by frequent premature ventricular complexes (PVCs) originating from the Purkinje system, atrial arrhythmias, and a predilection for PVC-mediated dilated cardiomyopathy. MEPPC-causative variants tend to cluster within the voltage sensing domain (VSD) of Na
v
1.5.

Objective:
To describe the clinical and cellular electrophysiological phenotype associated with a novel, putative MEPPC-causative
SCN5A
variant (p.Gln419Pro-SCN5A) that resides outside the VSD of Na
v
1.5.

Methods:
p.Gln419Pro-SCN5A was identified in a 21-year-old male with a history of frequent, multifocal PVCs and atrial tachycardia. Subsequently, three p.Gln419Pro-SCN5A-positive relatives, each with early onset atrial arrhythmias and/or frequent, multifocal PVCs, were identified. All individuals had structurally normal hearts by echocardiography and/or cardiac magnetic resonance imaging. p.Gln419Pro-SCN5A was engineered by site directed mutagenesis and heterologously expressed in TSA201 cells. The standard whole-cell patch clamp technique was used to measure SCN5A wild-type (WT) and p.Gln419Pro-SCN5A sodium currents.

Results:
Analysis of the current-voltage relationship revealed that neither peak sodium current densities nor late inward sodium current were impacted by p.Gln419Pro-SCN5A. However, p.Gln419Pro-SCN5A significantly shifted V
1/2
in inactivation by -4.6 mV from -84.5±0.7 mV (WT, n=10) to -89.1±0.4 mV (Gln419Pro, n=12, p<0.05 vs. WT) and V
1/2
in activation by -11.6 mV from -30.9±1.3 mV (WT, n=10) to -42.5±1.0 mV (Gln419Pro, n=12, p<0.05 vs. WT) leading to a larger hyperpolarized window current. Flecainide dramatically reduced PVC burden in p.Gln419Pro-SCN5A-positive patients.

Conclusions:
p.Gln419Pro-SCN5A represents only the fifth MEPPC-causative variant described to date and the first associated with a classic MEPPC phenotype localizing outside Na
v
1.5’s VSD. As class I antiarrhythmic drugs are highly efficacious in MEPPC, this clinical entity merits consideration in all young patients found to have a high burden of Purkinje-related PVCs.
Abstract 10584: Transitioning a Pediatric Cardiac Intensive Care Unit Rounding Checklist from Paper to the Electronic Health Record to Improve Utilization - A Quality Improvement Project
Authors: Mowrer Michael C , Shanmugham Prashanth , Patrick Joscyln , Huang Rong , Wolovits Joshua S , Hoffman Olivia L
Published: March 2022

Background:
Delivering excellent clinical care in a pediatric cardiac intensive care unit (PCICU) involves coordination of a multidisciplinary team and consistent implementation of best practices. A rounding checklist (RC) may mitigate failures in communication and reduce practice variability. Multiple barriers to successful RC utilization remain, including poor provider compliance.

Aim:
The primary aim of this quality improvement (QI) project is to implement and evaluate the utilization and effectiveness of an electronic health record (EHR)-based RC in the PCICU.

Methods:
In collaboration with key stakeholders, we used Plan-Do-Study-Act (PDSA) QI methodology to adapt our existing paper-based RC into an EHR-embedded tool (Fig 1). We conducted educational sessions prior to implementation of the RC to review its potential benefits. We evaluated project impact through pre- and post-implementation surveys of PCICU attendings, fellows and advanced practice providers. Our primary outcome metric was RC utilization.

Results:
Most pre-implementation survey respondents (n=33), agreed or strongly agreed that they would be interested in using a RC (78%), and it would be helpful (87%). During the first PDSA cycle, of 65 eligible patients, 74% (n=48) had the checklist completed at least once during their CVICU admission. Of 28 eligible providers during the same PDSA, 71% (n=20) completed a RC in the EHR at least once. Most survey respondents (n=25) after the first PDSA agreed or strongly agreed that using the RC is helpful (64%), easy (60%) and can be improved (60%). We continue to modify evaluate the RC and its utilization in subsequent PDSA cycles.

Conclusion:
Transitioning a RC from paper to the EHR is feasible and improves tracking of utilization. Engaging providers for feedback and making real-time modifications may improve future RC compliance. Continued data collection will improve our understanding of the RC’s impact on health care delivery and patient safety.
Abstract 10587: Frequency and Outcomes of Bradyarrhythmias in the Community
Authors: Haimovich Julian , Khurshid Shaan , Di Achille Paolo , Nauffal Victor , Singh Pulkit , Reeder Christopher , Harrington Lia , Wang Xin , Sarma Gopal , Kornej Jelena , Benjamin Emelia J , Philippakis Anthony A , Batra Puneet , Ellinor Patrick T , Lubitz Steven A
Published: March 2022

Introduction:
Bradyarrhythmias, diseases characterized by slow heart rates, are associated with substantial morbidity. Contemporary estimates of the frequency of bradyarrhythmias and associated outcomes in the community are needed.

Methods:
We examined the prevalence and incidence of bradyarrhythmias in a multi-institutional electronic health record cohort comprised of individuals receiving primary care. We used an automated tool to ascertain diagnoses from 12-lead electrocardiogram (ECG) diagnostic statements. We defined bradyarrhythmia groups based on location and severity of disease. We tested associations between clinical risk factors and incident bradyarrhythmia groups using multivariable proportional hazards regression. To characterize potential associations between bradyarrhythmias and major adverse cardiovascular events (MACE, a composite of myocardial infarction, heart failure, stroke, and death), we matched incident bradyarrhythmia and non-bradyarrhythmia individuals 1:1 on age, sex, and duration of preceding follow-up, and included bradyarrhythmia exposure in multivariable regression with MACE as the outcome.

Results:
Of a total of 520,868 individuals (mean age 48, 62% female, 3.5 million ECGs), the prevalence of any bradyarrhythmia was 10%. After excluding individuals with prevalent bradyarrhythmia, a total of 49,513 events occurred in 440,370 individuals as shown in Figure 1. Bradyarrhythmias were associated with common modifiable cardiovascular risk such as diabetes (HR 1.26, 95% CI [1.22-1.29]) and hypertension (HR 1.24, 95% CI [1.22-1.27]). Bradyarrhythmias were significantly associated with MACE in the atrioventricular delay (HR 1.07, 95% CI [1.01-1.14]) and conduction delay groups (HR 1.19, 95% CI [1.13-1.25]).

Conclusions:
Bradyarrhythmias are common and increase with older age and male sex. Incident bradyarrhythmias are associated with cardiovascular risk factors and may be associated with MACE.
Abstract 10602: Baseline Clinical and Genetic Data Based Machine Learning Predictions of 1-Year Ischemic Outcomes Following Percutaneous Coronary Intervention
Authors: Grant Caroline , Raina Anvi , Lennon Ryan , Goodman Shaun G , Gulati Rajiv , Lerman Amir , Rosenberg Yves , So Derek , Farkouh Michael E , Athreya Arjun , Pereira Naveen L
Published: March 2022

Background:
Ischemic event rates are low after percutaneous coronary intervention (PCI), conversely second generation P2Y12 inhibitors increase bleeding therefore identifying patients at risk to enable precision in prescribing dual anti-platelet therapy (DAPT) is of clinical interest. Prior machine-learning predictive analyses have been limited by use of older generation stents and lack of genetic data. We utilized clinical and genetic data of patients with new generation stents enrolled in TAILOR-PCI, a 40-center international trial to predict ischemic events after PCI.

Methods:
There were 4398 eligible post PCI patients with acute coronary syndromes or stable coronary artery disease who were randomly split into training (n=3299) and validation (n=1099) cohorts. The primary endpoint comprising of cardiovascular death, myocardial infarction, stroke, or stent thrombosis within 12 months of PCI was predicted with patient characteristics prior to hospital discharge. First, random forests were used for feature selection with 1,000 bootstraps comprising equal numbers of those with and without ischemic events to minimize the bias of sample imbalance. Features were selected by a consensus on variable-importance over bootstraps. Second, using these features in the training cohort, support vector machines (SVM) with a polynomial kernel was trained with repeated 5-fold cross validation to choose a model with highest area under the receiver operating characteristic curve (AUC) which was then used to predict ischemic events in the validation cohort.

Results:
The primary endpoint occurred in 2.4% of patients. Using 89 clinical and genetic variables in the random-forest feature selection step, variable importance-based consensus identified 50 top predictors. These 50 predictors achieved AUC=0.703 in the SVM training cohort and AUC=0.744 (specificity=0.84; sensitivity =0.43) in the SVM validation cohort.

Conclusions:
Machine learning methods using baseline clinical and genetic data enables prediction of infrequent ischemic events in post PCI patients receiving new generation stents. The role of such artificial intelligence algorithms in individualization of DAPT by identifying high or low risk patients needs to be explored.
Abstract 10603: Risk Factors for Development of Advanced Heart Failure: A Population-Based Study
Authors: Subramaniam Anna , Weston Susan , Killian Jill , Schulte Philip , Roger Veronique L , Redfield Margaret M , Blecker Saul , Dunlay Shannon M
Published: March 2022

Introduction:
Some patients with heart failure (HF) will go on to develop advanced HF, characterized by severe HF symptoms despite attempts to optimize medical therapy. Our understanding of advanced HF at a population level remains limited. The goals of this study were to determine the risk of developing advanced HF in patients with newly diagnosed HF, identify risk factors for developing advanced HF, and evaluate the impact of advanced HF on outcomes.

Methods:
This was a population-based, retrospective cohort study of Olmsted County, Minnesota residents with a new clinical diagnosis of HF between 2007-2017. The primary outcome was development of advanced HF, defined using the 2018 European Society of Cardiology Criteria. Risk factors for development of advanced HF from the time of incident HF diagnosis were examined using cause-specific Cox proportional hazard regression models. The associations of development of advanced HF with risks of hospitalization and mortality were examined using Andersen-Gill and Cox models, respectively, with advanced HF treated as a time dependent covariate.

Results:
There were 4597 residents with incident HF from 2007 to 2017. The cumulative incidence of advanced HF was 6.0%, 9.1%, and 11.5% at 2, 4, and 6 years after incident HF diagnosis. Characteristics independently associated with development of advanced HF included older age, male sex, diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, lower serum sodium, worse right ventricular function, left atrial enlargement, higher estimated filling pressures, and higher right ventricular systolic pressure (p<0.05 for each). Development of advanced HF was associated with increased risks of all-cause hospitalization (adjusted HR 3.00; 95% CI 2.65-3.41, p<0.001), HF hospitalization (HR 10.24, 95% CI 8.67-12.10), all-cause mortality (HR 5.00, 95% CI 4.46-5.59, p<0.001), and cardiovascular mortality (HR 7.84, 95% CI 6.74-9.12).

Conclusions:
In this population-based study, clinical, laboratory and echocardiographic characteristics at the time of incident HF diagnosis were associated with future risk of advanced HF. Development of advanced HF was associated with markedly increased morbidity and mortality.
Abstract 10605: Artificial Intelligence Effectively Measures Left Atrial Volumes and Function on Multiphasic Cardiac Cta in Patients with Atrial Fibrillation
Authors: Aquino Gilberto , Yacoub Basel , Kocher Madison , Chamberlin Jordan , Kabakus Ismail Mikdat , Akkaya Selcuk , Mercer Megan , Waltz Jeffrey , Figel Matthew , Leaphart Nathan , Jacob Athira , Gulsun Mehmet A , Gilkes James , Stephenson Joseph , Sharma Puneet , Sahbaee Pooyan , Field Michael E , Agha Ali M , Schoepf Joseph , baruah dhiraj , Emrich Tilman , Burt Jeremy R
Published: March 2022

Introduction:
This study was performed to evaluate a novel AI algorithm for fully automated measurement of LA volumes and function using cardiac CTA in patients with atrial fibrillation (AF).

Methods:
A prototype AI algorithm (AI-LAV), with a conditional variational auto-encoder architecture, was developed and trained using 555 manually annotated ECG-gated, contrast-enhanced cardiac CTs. A total of 79 patients (mean age 63 ± 12 years; 35 with AF and 44 controls) evaluated between 2017 and 2020 were included in this retrospective study to validate the AI model. Images were analyzed by the trained AI algorithm and experienced radiologists. Left atrial volumes were obtained at cardiac end-systole (LAVmax), end-diastole (LAVmin), and pre-atrial contraction (LAVpc), which were then used to obtain LA function indices (total, passive, and active emptying fractions). Statistical analysis was performed.

Results:
AI was significantly faster than manual measurement of LA volumes and function (4 s vs 10.8 min, respectively). Agreement between the manual and automated methods was good to excellent overall, and there was stronger agreement in AF patients (all ICCs ≥ 0.877; p<0.001) than controls (all ICCs ≥ 0.799; p<0.001). The AI comparably estimated LA volumes and function in AF patients (all within 1.3 mL and 1.7% of the manual measurement), but overestimated volumes and function by clinically negligible amounts in controls (all by ≤ 4.2 ml and ≤ 3.5%). The AI’s ability to distinguish AF patients from controls using the LA volume index was similar to the experts’ (AUC 0.81 vs 0.82, respectively; p = 0.62).

Conclusion:
In a validation cohort, the novel AI algorithm efficiently performed fully automated multiphasic CTA-based quantification of left atrial volume and function with similar accuracy to expert manual quantification.

Figure.
Scatter and Bland-Altman plots for LAVmax and LAVmin. Segmentation comparison between expert (manual) and AI on cardiac CTA.