bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11900: Should Venous Thromboembolism Patients Treated With DOACs Be Dose Adjusted Like Patients With Atrial Fibrillation: Lessons From Apixaban
Authors: Baruch Lawrence , Ofoche Obinna , Sherman Olga , Lopez Loyo Persio D
Published: June 2023

Introduction:
In contrast to atrial fibrillation (AF), dose adjustment of apixaban and other DOACs is not recommended for pts with DVT or PE (VTE). Median DOAC levels were lower in VTE trials (e.g. apixaban 5-mg BID, AF 171 and 103 ng/mL vs. DVT 132 and 63 ng/mL, peak and trough, respectively), the result of a younger, lower weight population with better kidney function. Thus, VTE patients who meet or approach the apixaban dose reduction criteria may have levels far in excess of what’s needed to prevent recurrence.

Hypothesis:
Apixaban over exposure occurs in VTE pts at risk for elevated apixaban levels.

Methods:
Patients ≥ 75 yrs of age who had clinical markers that identified them as being at high risk for over exposure, including: 1) apixaban AF dose risk reduction criteria (age ≥ 80, creatinine ≥ 1.5, and wt ≤ 60-kg) and 2) approaching but not meeting dose reduction criteria (e.g. creatine 1.4, weight 65-kg) had a DOAC level measured at their anticoagulation clinic appointment. Levels were determined using liquid chromatography-mass spectrometry. Clinical decisions were made based on the “expected” apixaban levels.

Results:
Apixaban levels were obtained in 15 male pts. All 10 pts who were initially treated with apixaban 5-mg (2 of whom met the AF dose reduction criteria) had supratherapeutic apixaban levels on 5-mg BID. Of the 5 pts treated initially with apixaban 2.5-mg BID, 3 had adequate apixaban levels, while the other 2 had trough levels that were on the lower side. All 3 pts who met the AF dose reduction criteria (1 treated initially with 2.5-mg) had an adequate apixaban level on 2.5-mg BID.

Conclusions:
Apixaban treated VTE pts who meet or approach the AF dose reduction criteria are candidates for apixaban dose reduction, especially in light of the fact that peak and trough levels for VTE pts in general are lower than pts with AF.
Abstract 11912: Pregabalin Use Increases the Risk of Acute Heart Failure in Patients With Heart Failure: A Population-Based Study
Authors: Wynn Emma , Biskupiak Jospeh , Kim Kibum , Munger Mark A
Published: June 2023

Introduction:
Pregabalin, a structural analog to λ-aminobutyric acid, is prescribed for neurological disorders. Through actions to cause sodium/water retention, the agent may increase the risk of acute heart failure (AHF).

Methods:
We performed a retrospective cohort study using a repository of healthcare records obtained from a large U.S. academic healthcare system. HF patients were identified between 1/1/2016-12/31/2020. Patients who had initiated treatment with pregabalin were compared to patients with no post-HF pregabalin over a 365-day post-pregabalin period or post-HF period. Study outcomes were per-patient per-year (PPPY) emergency department (ED) admissions or PPPY hospitalizations, time-to first ED admission, and time-to hospitalizations. Outcomes encounters were adjudicated by a HF diagnosis (ICD-10, I50.x) at any position. We tested the association between the pregabalin exposure and outcomes using generalized linear regression and Cox-proportional hazard regression approach.

Results:
The study cohort included 483 pregabalin-HF patients and 21,150 pregabalin-naïve HF patients. The pregabalin-HF patients age was (mean±SEM: 62.2±0.7 vs. 66.2±0.1 years,
p
<0.0001) and more females (54.9% vs, 44.4%,
p
<0.0001) than pregabalin-naïve HF patients. Charleston comorbidity score was 3.66±0.14 vs. 3.23±0.02 (
p
=0.007). Pregabalin use was associated with a 13% increase in PPPY AHF hospitalizations (
p
<0.036). A 15% increase in the PPPY ED pregabalin admissions was noted (
p
=0.1142). Pregabalin ED admission or AHF hospitalization were 1.492 (95% CI: 1.204 ̶ 1.850 [
p
=0.0003]) and 1.112 (95% CI: 0.922 ̶ 1.340 [
p
=0.2663]).

Conclusion:
This retrospective cohort study shows pregabalin is associated with an increased risk of AHF in patients with existing HF. Pregabalin prescribing in HF should be considered with caution. Further signal evaluation to test the robust association between pregabalin and AHF is warranted.
Abstract 11922: The Independent Effects of Race/Ethnicity and Local Childhood Opportunity on Outcomes in Pediatric Congenital Heart Surgery
Authors: Elfituri Mahmud , Zaniletti Isabella , Ressler Robert W. , Noelke Clemens , Gelb Bruce , Pass Robert , Seiden Howard , Duong Son
Published: June 2023

Background:
Disparities in congenital heart disease (CHD) outcomes based on race/ethnicity and social determinants of health coexist. We sought to determine the independent effects of these factors on outcomes after pediatric CHD surgery.

Methods:
Pediatric Health Information System encounters age <18 years from 2003-2022 with ICD9/10 codes for CHD and cardiac surgery were linked to Zip Code-level Childhood Opportunity Index (COI), a score of neighborhood educational, environmental, and socioeconomic conditions. Independent effects of race/ethnicity and COI quintile on the outcome of death during surgical hospitalization were modeled with generalized estimating equations. Survival in neonates was modeled with Cox PH regression.

Results:
Of 193,028 encounters at 46 centers, Black, Asian, and Other groups had increased adjusted mortality compared to Non-Hispanic (NH) White. Compared to the middle COI quintile, the lowest quintile had a higher adjusted risk of death and the highest quintile was protective (Table 1a). In survival analysis of neonates (n=47,649; median follow-up 1.1 years), Black, Asian, and “Other” groups had worse survival than NH-White even after adjustment for COI quintile (Table 1b, Figure 1).

Conclusions:
Black, Asian, and “Other” children have increased in-hospital death after CHD surgery independent of local opportunity. Medium-term survival after neonatal surgery is similarly influenced, suggesting local opportunity is influential even at birth. Policies to improve local social determinants of health may improve outcomes, but persistent negative effects of minority status may be explained by other unmeasured forms of structural racism.
Abstract 11943: MCUF-651: A Novel Natriuretic Peptide Receptor A (NPRA) Small Molecule Positive Allosteric Modulator With Blood Pressure Lowering and Renal Enhancing Properties in Experimental Hypertension
Authors: Ma Xiao , Moroni Dante , Peddibhotla Satyamaheshwar , Ma Xiaoyu , Zheng Ye , Pan Shuchong , Burnett John C , Malany Siobhan , Sangaralingham Jeson
Published: June 2023

Introduction:
Hypertension (HTN) represents one of the greatest burdens in human health and is associated with increased morbidity and mortality. Despite the availability of several antihypertensive drugs, most patients have suboptimal blood pressure (BP) control, thus underscoring the need for new therapeutic drugs. The natriuretic peptide receptor A (NPRA) possesses potent vasodilating, natriuretic and diuretic actions via activation by ANP or BNP and generation of its second messenger, cGMP. Recently, we reported the discovery of a small molecule positive allosteric modulator (PAM) for NPRA, MCUF-651, which enhances the ANP/BNP/NPRA/cGMP pathway (PNAS,2021). To date, the in vivo actions of MCUF-651 remains unknown. Here we tested the hypothesis that MCUF-651 would have BP lowering and renal enhancing properties in experimental HTN.

Methods:
A single IV bolus of MCUF-651 (10mg/kg; n=4) or vehicle (V; n=5) was injected into anesthetized spontaneous hypertensive rats (SHRs). Plasma and urinary cGMP (PcGMP and UcGMP), mean arterial pressure (MAP) and urinary volume (UV) and sodium (UNa) excretion were assessed at baseline (BL) and over 60-mins post-bolus.

Results:
In SHRs, PcGMP and UcGMP were significantly elevated with MCUF-651 compared to the vehicle group (ΔPcGMP MCUF-651: 16±5, ΔPcGMP V: -2±3, pmol/mL;
P
=0.003; ΔUcGMP MCUF-651: 78±29, ΔUcGMP V: 30±8, pmol/min,
P
=0.01), thus supporting NPRA target engagement. Notably, the elevations in cGMP with MCUF-651 were associated with a significant reduction in MAP at 15-mins post bolus compared to vehicle (ΔMAP MCUF-651: -29±14, ΔMAP V: -6±2 mmHg;
P
=0.04) and this MAP reduction was sustained over 60 mins. Further, UV and UNa excretion were significantly increased, from BL, with MCUF-651 (BL UV: 6 ± 2, 60 mins post bolus UV: 56± 18 μL/min,
P
<0.001; BL UNa: 1±0.2, 60 mins post bolus UNa: 8±2 μmol/min,
P
<0.001).

Conclusions:
We report for the first time that MCUF-651, a novel NPRA small molecule PAM, engages NPRA, increases cGMP and reduces MAP while enhancing sodium and water excretion in experimental HTN. These findings support the development of MCUF-651 as a potential new therapeutic modality to optimize BP lowering goals and reduce adverse outcomes in human HTN.
Abstract 11953: Sudden Death Associated With Therapeutic Levels of Methadone: Significance of Drug Interactions
Authors: Norby Faye L , Reinier Kyndaron , Hennessy Sean , Uy-Evanado Audrey , Chugh Harpriya , Sargsyan Arayik S , Salvucci Angelo , Jui Jonathan , Hurst Sean , Young Christopher , Chugh Sumeet S
Published: June 2023

Introduction:
Methadone for treatment of addiction or chronic pain can be complicated by QT interval prolongation and increased risk of sudden cardiac death (SCD). The concurrent use of additional QT-prolonging medications, such as selective serotonin reuptake inhibitors (SSRIs), may contribute to additional increased risk. We conducted a community-based study to assess the potential role of drug combinations in SCD.

Methods:
We ascertained residents of Multnomah Co., OR (2002-18) and Ventura Co., CA (2015-21) who suffered SCD and had toxicology reports available. We excluded those under age 18 and those with evidence of recreational drug use or drug overdose. Methadone levels and medications were captured on toxicology reports from the medical examiner. We used logistic regression to compare characteristics and the presence of select medications in those with and without therapeutic levels of methadone at the time of SCD.

Results:
Of the 789 subjects who met our criteria, the mean (25th-75th percentile) age was 49 (39-59) years, 34% were females, and 85 (11%) had therapeutic levels of methadone. Subjects on methadone were younger, more likely to be female, and had a higher prevalence of SSRIs and benzodiazepines compared to those without methadone (Table). Subjects with methadone had a 3.37 higher odds of SSRI use compared to those without methadone (95% CI: 1.87-6.09). When stratified by mechanistic category, those with methadone had higher odds of QT-prolonging SSRIs [OR (95% CI) = 2.87 (1.35-6.13)] and higher odds of other SSRIs [OR (95% CI) = 3.20 (1.40-7.32)] compared to those without methadone. Combinations of methadone with other selected drug classes did not reach statistical significance.

Conclusion:
These postmortem findings suggest that the combination of methadone with SSRIs may be associated with additional risk of SCD and warrant further investigation. Drug interactions are a potentially avoidable risk factor for SCD in patients receiving methadone.
Abstract 11956: Blood DNA Methylation Predicts Differential Metabolic Outcomes Induced by Different Types of Weight-Loss Intervention: Findings From an Epigenome-Wide Association Study
Authors: Wen Xiaoxiao , Palma-Gudiel Helena , Miao Guanhong , Chen Mingjing , Huo Zhiguang , Peng Hao , Anton Stephen , Hu Gang , Brock Ricky , Brantley Phillip J , Zhao Jinying
Published: June 2023

Background
Previous epigenetic studies in obesity interventions have focused on the intervention-associated DNA methylation (DNAm) changes, yet whether the DNAm before intervention could be used as a predictor of prognosis has not been investigated. Here we hypothesize that baseline DNAm can predict differential metabolic outcomes, i.e., changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), induced by different weight-loss interventions.

Methods
The analyses included 75 individuals with obesity in the HeadsUp Study, a longitudinal study assessing the effectiveness of different weight-loss interventions, from the non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) and Roux-en-Y gastric bypass (RYGB) groups (n = 25 per group). Genome-wide DNAm was determined using baseline blood samples, while changes in FPG and HbA1c were measured at 1-year follow-up. Epigenome-wide association studies were performed on 455,983 CpGs to identify DNAm predictors of differential metabolic outcomes, adjusting for age, sex, BMI, FPG/HbA1c at baseline, weight loss and batch effect.

Results
DNAm levels at 3,216 and 117 CpG loci significantly predicted differential changes in FPG and HbA1c, respectively, when comparing RYGB vs. IMI groups, but not in other group comparisons (RYGB vs. BAND or BAND vs. IMI, with the exception of 6 CpGs identified for HbA1c changes when comparing RYGB vs. BAND), after FDR correction for multiple testing. Of these, altered DNAm at 79 CpGs significantly predicted changes in both FPG and HbA1c (RYGB vs. IMI). These CpGs were annotated to 68 genes, among which the most significant ones were
SNX18, LNPK, CCDC178, ADAM7
and
ZNF23
. These genes are mostly involved in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation.

Conclusions
To our knowledge, this is the first study demonstrating that baseline blood DNAm predicts differential metabolic outcomes induced by different types of weight-loss interventions, independent of weight loss. Such results help explain, at least partly, the favorable metabolic outcomes of RYGB over other types of weight-loss intervention (e.g., BAND, IMI), and are likely to lead to precision strategies for obesity treatment.
Abstract 11959: Cardiopulmonary Exercise Testing Delineates Multiple Contributing Factors to Poor Exercise Performance in Childhood Cancer Survivors
Authors: Tsuda Takeshi , D Aloisio Gina , Quillen Joanne
Published: June 2023

Background:
Childhood cancer survivors (CCS) show decreased exercise performance despite normal ventricular function at rest. Multiple underlying mechanisms are considered.

Methods:
Cardiopulmonary exercise testing (CPET) was performed in asymptomatic off-treatment CCS. Patients were divided into four groups by their peak oxygen consumption (pVO2) at 35 and 25 ml/kg/min in males and females, respectively (“Good” and “Poor” performance groups). * denotes weight-indexed values. Data are shown as mean ± standard deviation.

Results:
Demographic and CPET data are presented in Table 1. There was no notable correlation between total anthracycline dosage and CPET values. Weight, body mass index, and peak respiratory exchange ratio were significantly higher in “Poor” groups in both sexes. Peak oxygen pulse (pOP*) and ventilatory anaerobic threshold (VAT*) were significantly lower whereas heart rate (HR) dependency on work rate (WR*) (= ΔHR/ΔWR*) was significantly higher in “Poor” groups than in “Good” groups. There was no difference in ventilatory efficiency presented as a slope of ventilation (VE)/carbon dioxide output (VCO2)(ΔVE/ΔVCO2). Figure 1 demonstrated the relationship between weight and pVO2 (L/min) and between ΔHR/ΔWR* and pOP*, showing distinct difference between “Good” and “Poor” performers in both sexes; “Poor” performers revealed lower skeletal mass and stroke volume effects.

Conclusions:
Treatment-mediated cardiotoxicity is not the only cause of poor exercise performance in CCS. In addition to limited stroke volume indicated by lower pOP* with higher HR dependency, skeletal muscle loss and increased BMI mitigated the overall exercise performance.
Abstract 11962: Cardiopulmonary Exercise Testing Predicts Mortality in Cardiac Amyloidosis: A Systematic Review and Meta-Analysis
Authors: Cantone Anna , Rapezzi Claudio , Agostoni Piergiuseppe , Sanguettoli Federico , Pavasini Rita , Maio Daniele , Di Ienno Luca , Fabbri Gioele , GUARDIGLI GABRIELE , Campo Gianluca , Serenelli Matteo
Published: June 2023

Introduction:
The cardiopulmonary exercise testing (CPET) has been proved to be a good tool in prognostic stratification of HFrEF and HFpEF, but its value in cardiac amyloidosis (CA) is uncertain. With the increasing knowledge and clinical suspicion toward CA, the growing prevalence of the disease, and the current availability of disease-modifying drugs, prognostic stratification is becoming fundamental to optimise the cost-effectiveness of treatment, patient follow-up and management.

Hypothesis:
We investigate the association of VO2max and VE/VCO2 slope with prognosis in patients with CA.

Methods:
We performed a systematic review following the PRISMA guidelines. Electronic databases (MEDLINE, Biomed Central, and Cochrane Library) were searched for clinical trials performing CPET for prognostication in transthyretin and light-chain CA patients. Studies reporting Hazard Ratio (HR) for mortality and VO2 max or VE/VCO2 slope (1-unit increase) were further selected for quantitative analysis. After logarithmic transformation, HRs were pooled using a random-effect model.

Results:
Five studies were selected for qualitative analysis and 3 for the quantitative analysis. A total of 233 patients were included in the meta-analysis, 127 (55%) with transthyretin and 106 (45%) with light-chain CA. Mean VO2 max in each trial was consistently depressed, ranging from a mean of 14.5 ± 4.5 mL/kg/min to 15.2 ± 10 mL/kg/min. On the other side, the VE/VCO2 slope ranged from a mean of 30 ± 3.0% to 41.3 ± 9.7%. Our pooled analysis shows that VO2 max (pooled HR 0.89, 95%CI 0.84-0.94) and VE/VCO2 slope (pooled HR 1.04, 95%CI 1.01-1.07) are significantly associated with the risk of death in CA patients, with no significant statistical heterogeneity for both analyses.

Conclusions:
CPET is a valuable tool for prognostic stratification in CA, identifying patients at increased risk of death. Large prospective clinical trials are needed to confirm this exploratory finding.
Abstract 11965: Cellular Senescence Produces Diastolic Dysfunction and Cardiac Hypertrophy With Aging in Mice
Authors: Mehdizadeh Mozhdeh , Mackasey Martin , Tardif Jean-Claude , Naud Patrice , Ferbeyre Gerardo , Sirois Martin , Thorin Eric , Tanguay Jean-Francois , Nattel Stanley
Published: June 2023

Background:
Age is a major risk factor for heart failure with preserved ejection fraction (HFpEF); however, the underlying mechanisms are poorly understood. Cellular senescence is an aging and stress related response; senescent cells (SCs) secrete bioactive substances that produce a variety of pathological changes. The role of senescence in HFpEF is unknown.
Objectives:
To study the effect of targeted deletion of SCs on cardiac function, structure and left ventricular (LV) pressure in an aging mouse model of HFpEF.

Methods:
We studied INK ATTAC mice, in which SCs undergo targeted clearance following treatment with a dimerizing agent, AP20187 (AP). Mice were treated with blinded AP or vehicle from 12 months to 18 months of age. Cardiac function and structure were studied with echocardiography. Contractility parameters were measured with a Millar catheter. The percentage of SCs in different cardiac-cell populations was analyzed with the use of Fluorescence-Activated Cell Sorting (FACS).

Results:
From 12 to 18 months, LV mass/LV diameter at end diastole (LVDd) and the LV anterior wall thickness at end diastole (LVAWd) increased in the vehicle group while they decreased in the AP group (LV mass/LVDd: %Δvehicle=+7.9± 3%, %ΔAP=-2±1.2%, P=0.005; LVAWd: %Δvehicle=+5.3±2.5%, %ΔAP=-3.5±1.6%, P=0.007) (Fig1A, B). E/e’ (echo) and isovolumic relaxation time indicated diastolic dysfunction in vehicle mice, and improved with AP (Fig1C, D). GFP bicistronic with p16 indicated SCs; FACS-purified fibroblasts (FBs) showed reduced GFP fluorescence (P=0.056) in the AP group, whereas immune and endothelial cells were not affected, suggesting that the anti-HFpEF effects of SC-clearance might be mediated through the clearance of senescent FBs (Fig1E).

Conclusions:
Our study points to a significant role of SCs, likely senescent FBs, in the pathophysiology of HFpEF. Modulating senescence might provide the basis for novel therapeutic approaches to HFpEF prevention and/or therapy.
Abstract 11974: A Randomized, Controlled Trial of Resistance Training Added to Caloric Restriction Plus Aerobic Exercise Training in Obese Heart Failure With Preserved Ejection Fraction
Authors: Brubaker Peter H , Nicklas Barbara , Houston Denise , Hundley William G , Chen Haiying , Molina Anthony , Lyles Mary , Nelson Michael , Upadhya Bharathi , Newland Russ , Kitzman Dalane W
Published: June 2023

Background:
We previously showed that the combination of caloric restriction (CR) and aerobic exercise training (AT) produce robust improvements in exercise capacity and quality of life (QOL) in patients with obese Heart Failure with Preserved Ejection Fraction (HFpEF). However, ~ 35% of weight lost during CR+AT was from skeletal muscle (SM) mass, which may have adverse long-term consequences.

Hypothesis:
The addition of resistance training (RT) to CR+AT would reduce SM loss and further improve exercise capacity and QOL.

Methods:
Randomized, controlled, single blind trial of 20 weeks of RT+CR+AT vs. CR+AT in 88 patients with HFpEF and body mass index (BMI) ≥28 kg/m
2
. Measurements were: peak exercise O
2
consumption (VO
2
); body composition by MRI and dual X-ray absorptiometry; leg muscle strength; leg muscle quality (leg strength ÷ leg SM area); Kansas City Cardiomyopathy Questionnaire (KCCQ) total score.

Results:
77 participants completed the trial: age 68±5 years; 85% women; BMI 39.6±5.8 kg/m
2
. Both RT+CR+AT and CR+AT had substantial weight loss, mean (95% CI): -8.1 (-9.3, -6.8) vs. -9.2 (-10.5, -7.9) kg with no significant intergroup difference (p=0.21). Both RT+CR+AT and CR+AT had substantial loss of total body fat [-6.5 (-7.2, -5.8) vs. -7.4 (-8.1, -6.7) kg] and SM [-2.1 (-2.7,- 1.5) vs. -2.1 (-2.7, -1.4) kg], with no intergroup differences (p=0.20 and 0.23, respectively). Despite similar relative loss of SM (26% vs. 23% of total weight lost), RT+CR+AT vs. CR+AT alone produced significantly greater increases in leg muscle strength [4.9 (0.7, 9.0) vs. -1.1 (-5.5, 3.2) Nm, p=0.05] and leg muscle quality [0.07 (0.03, 0.11) vs. 0.02 (-0.02, 0.06) Nm/cm
2
, p=0.04]. Both RT+CR+AT and CR+AT produced large, significant improvements in peak VO
2
[108 (958, 157) vs. 80 (30, 130) ml/min; p=0.001 and 0.002, respectively], and in KCCQ score [17 (12, 22) vs. 23 (17, 28); p=0.001 for both], with no significant intergroup differences (p=0.21 and p=0.07, respectively). There were no study related serious adverse events.

Conclusion:
In older obese HFpEF patients, CR+AT produces large, significant improvements in exercise capacity and QOL. Addition of RT to CR+AT increased leg strength and leg muscle quality without attenuating SM loss or further increasing peak VO
2
or KCCQ score.
Abstract 11978: Composite Deep Learning ECG Algorithm Trained to Identify Structural Heart Diseases Can Identify Clinically Ascertained Hypertrophic Cardiomyopathy
Authors: Lee Greg , Kang Martin , Ulloa Cerna Alvaro , Hartzel Dustin , Rocha Daniel , Nemani Arun , Fornwalt Brandon , Chen Ruijun , Pfeifer John , Haggerty Christopher M
Published: June 2023

Introduction:
A deep learning ECG algorithm, rECHOmmend, can accurately identify patients with any of seven structural heart diseases: five valvular diseases, low ejection fraction and interventricular septal (IVS) thickening. Components of the rECHOmmend composite label (IVS>15mm, mitral regurgitation) are also associated with hypertrophic cardiomyopathy (HCM). We hypothesized that despite being trained without HCM-specific labels, rECHOmmend can reliably identify HCM patients and achieve comparable performance to an HCM-specific classifier.

Methods:
Algorithms were developed from 2,898,979 ECGs acquired from 661,366 patients between 1984-2021. rECHOmmend was trained on a composite label derived from echocardiography and electronic health record (EHR) data. This ensemble model consists of 7 disease specific models with an aggregate model to predict a composite structural heart disease endpoint with shared clinical actionability. Separately, an HCM-specific model was trained on a binary label derived from EHR. To enable comparison, both classifiers were tested on a shared ECG holdout set (ECG prevalence 1.24%, patient prevalence 0.52%).

Results:
Despite being trained without HCM specific labels, the rECHOmmend ensemble showed comparable performance to a HCM-specific classifier (C-statistic: 0.92 [0.90-0.93] vs 0.90 [0.89-0.91]). At an operating point optimized for the F1-score, the sensitivity to HCM was higher for rECHOmmend at 0.42 [0.33-0.50] compared to 0.18 [0.15-0.21] for the HCM-specific classifier. rECHOmmend sustained performance across a range of IVS thicknesses, suggesting it was not solely reliant on IVS thickening for HCM identification and other ensemble components contributed to performance.

Conclusions:
A composite deep learning algorithm trained to identify structural heart diseases can identify clinically ascertained HCM with good performance, despite being trained without HCM-specific labels.
Abstract 11979: Direct Assessment of Engineered Heart Tissue Field Potential and Contraction Dynamics Using Flexible Electronics Technology
Authors: Fullenkamp Dominic E , Oh Seyong , Park Yoonseok , Chychula Ivana A , Holgren Cory W , Curtin Jodi L , Demonbreun Alexis R , Rogers John A , McNally Elizabeth M
Published: June 2023

Introduction:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enable the study of human heart disease in a dish. However, when cultured as cells on plastic, these 2D models are immature and exhibit non-physiologic outputs. When cultured as engineered heart tissues (EHTs or 3D models), hiPSC-CMs display a more mature gene and protein profile. Although multielectrode array (MEA) platforms have been applied to 2D cultures to study the electrical properties of hiPSC-CMs, a similar approach has been lacking for EHTs. We now took advantage of technological advances in flexible electronics to create a 3D platform that allows continuous transduction of field potential and strain of human EHTs.

Methods and Results:
Using microfabrication techniques adapted from the semiconductor industry, custom ring-shaped flexible electronics constructs were created with 6 support posts. Each post included a microelectrode for recording electrophysiological information and a piezoresistive strain sensor for monitoring EHT contraction dynamics. These were integrated onto a flexible biocompatible polyimide support. hiPSCs were differentiated into hiPSC-CMs, and EHTs were generated by seeding 500,000 cells composed of 90% hiPSC-CMs and 10% human cardiac fibroblasts into a collagen matrix and deposited in the ring-shaped polydimethylsiloxane (PDMS) molds. Tissues were condensed over 7 days and then were transferred onto the flexible electronic scaffolds. Tissues remodeled for ~30 days and then were analyzed for contractile properties. Direct tissue stimulation and field potential measurements were obtained in real time using an Intan RHS stimulation recording system. Simultaneous recording of force of contraction relied on a calibrated Wheatstone bridge circuit. EHTs from hiPSC-CMs displayed appropriate contractile responses to pharmacologic agents.

Conclusion:
Although EHTs improve hiPSC-CM models by improving cellular maturity, it has been challenging to measure physiological outcomes. We now developed a prototype that simultaneously provides electrophysiologic and contractility characterization in real time of human EHTs.
Abstract 11982: Clinical Outcomes of Outpatients With Suspected Covid-19 Treated With Chloroquine Compounds in Brazil: A Nationwide Telemedicine Study
Authors: Nascimento Bruno R , Paixao Gabriela , Tonaco Luís Antônio B , alves ana carolina D , Peixoto David C , Ribeiro Leonardo B , Santos Mendes Mayara , Gomes Paulo R , Pires Magda C , Ribeiro Antonio L
Published: June 2023

Introduction:
Following the inception of the COVID-19 pandemic, chloroquine compounds were proposed as potential therapeutic strategies, at the cost of a potential increase in cardiovascular risk. We aimed to evaluate clinical outcomes of patients with COVID-19, comparing those using chloroquine compounds to individuals without specific treatment.

Methods:
Outpatients with suspected COVID-19 in Brazil who had at least 1 ECG transmitted to a Telehealth Network, were prospectively enrolled in 2 arms (G1: treatment with chloroquine compounds and G2: without specific treatment) and G3: registry of other specific treatments. Outcomes were assessed through follow-up phone calls on days 3 and 14, and also administratively collected from national mortality and hospitalization databases. The primary outcome was composed of: hospitalization and all-cause death. The association between treatment groups and the primary outcome was evaluated by logistic regression. Significant variables (p<0.10) were included in 4 multivariate models: 1: unadjusted; 2: adjusted for age and sex; 3: adjusted for model 2 plus cardiovascular risk factors and 4: adjusted for model 3 plus COVID-19 symptoms (when available from phone contact).

Results:
In 303 days, 712 (10.2%) patients were allocated in G1 (chloroquine), 3623 (52.1%) in G2 (control) and 2622 (37.7%) in G3 (other treatments). Median age was 49 (IQR 38 - 62) years, 57% women. Of these, 1969 had successful phone contacts (G1: 260; G2: 871; G3: 838). The primary outcome was more frequent in groups 1 and 3 compared to the control group, when assessed exclusively by phone (G1: 38,5% vs. G2: 18,0% vs. G3: 34,2%, p<0,001) or combined with administrative data (G1: 19,5% vs. G2: 11,0% vs. G3: 18,2%, p<0,001). In the adjusted models, chloroquine independently associated with a greater chance of the primary outcome: phone contact (model 4): OR=3.24 (95% CI 2.31 - 4.54), p<0.001; phone + administrative data (model 3): OR=1.99 (95% CI 1.61 - 2.44), p<0.001. Chloroquine also independently associated with higher mortality, as assessed by phone + administrative data (model 3): OR=1.67 (95% CI 1.20 - 2.28).

Conclusion:
Chloroquine compounds associated with a higher risk of poor outcomes in outpatients with COVID-19 compared to standard care.
Abstract 12017: The Prognostic Role of Genotypic Variants of ACE2 and TMPRSS2 Polymorphisms in SARS-CoV2 / COVID-19 Infection
Authors: Fioretti Francesco , Sammartino Antonio Maria , Ravasio Francesco , Praderio Angelica , Inama Lorenza , Pagnesi Matteo , Pallotti Francesco , Nodari Savina
Published: June 2023

BACKGROUND:
the entry of the SARS-CoV-2 into cells is mediated by the binding between the virus Spike-glycoprotein and the membrane ACE2-receptor (ACE2-R). When SARS-CoV-2 binds to ACE2-R, a down-regulation of these receptors occurs, playing a crucial role in the inflammatory response. A dysregulation of the RAAS linked to a different expression of ACE2-R and TMPRSS2 gene polymorphisms and different levels of serum ACE2 (sACE2), could be associated with abnormal inflammatory and immune response to SARS-CoV-2 infection.
AIM OF THE STUDY:
we aimed to verify whether there is an association between the clinical course of COVID-19 pts and the presence of more frequent ACE2 and TMPRSS2 single-nucleotide polymorphisms (SNPs) and if sACE2 levels are related to specific ACE2 and TMPRSS2 polymorphic variants.

Methods:
we consecutively enrolled subjects with previous documented SARS-CoV-2 infection and divided our sample into three groups: pts with asymptomatic course; pts with symptomatic course without an hospitalization for COVID-19; pts with severe symptomatic course requiring hospitalization in ICU. Data about age, clinical course, comorbidities, and therapies were collected. Blood samples were taken for the genetic analysis of the most frequent SNPs of the ACE2-R and TMPRSS2 detected in Italian population, in particular genotypic variants TT and CC of ACE2 SNPs 1 and 5 (5% and 14% respectively) and genotypic variants TT and CC of TMPRSS2 SNPs 2 and 3 (rate of 50% and 30% respective).

Results:
among 178 pts enrolled up to March 2022, we have so far analyzed the genetic polymorphisms of 74 pts; 21 (28%) were hospitalized for COVID-19, 38 (51%) had symptomatic course without hospitalization and 15 (21%) were completely asymptomatics. We found that sACE2 levels were higher in genotypic variant CC of SNP 1 of TMPRSS2 gene. Considering that a high concentration of sACE2 outlines a proinflammatory condition, it could be hypothesized that the CC genotype may be a predisposing condition to the cytokine storm of COVID-19.
PERSPECTIVES:
Genetic analysis of ACE2 and TMPRSS2 SNPs will help to clarify the relationship between these polymorphic variant, sACE2 levels, risk of SARS-CoV2 infection and severity of clinical presentation of COVID-19 in pts with or without CV diseases.
Abstract 12022: Predictors of Mortality in Patients With Biopsy-Proven Cardiac AL Amyloidosis
Authors: Koutroumpakis Efstratios , Niku Adam , Black Christopher K , Sadaf Humaira , Song Juhee , Palaskas Nicolas L , Iliescu Cezar , Durand Jean-Bernard , Deswal Anita M , Buja Louis M , Banchs Jose
Published: June 2023

Introduction:
Cardiac involvement occurs in ~50% of patients with light-chain (AL) amyloidosis and conveys a poor prognosis. This study examined the role of histopathologic and echocardiographic parameters in predicting mortality.

Methods:
Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at MD Anderson Cancer Center between 6/2011 and 6/2020 were identified. Stored echocardiographic images were processed for longitudinal strain (global [GLS], apical, mid, basal) as well as radial and circumferential strain of the left ventricle (LV), right ventricle (RV) free wall, left atrium (LA), and right atrium, using the Epsilon EchoInsight Software. A detailed histomorphologic characterization of stored endomyocardial biopsy samples was performed by a cardiac pathologist and scored as < or > 5% AL deposits.

Results:
We identified 43 patients; 44% were women and 63% white. Median age was 65 years (IQR 59-70). Twenty-two (51%) underwent stem cell transplantation (SCT). A total of 29 patients (67%) died during follow up period (median follow up: 4.2 years (95% CI, 2.8-8.6)). Median overall survival (OS) was 18 months (95% CI, 8.1-37). Lower LA GLS and absence of SCT as a time-varying covariate were significantly and independently associated with increased risk of death in the multivariable cox regression analysis (HR 3.8, 95% CI 1.4-10.2 for LA GLS
<
13.5 vs >13.5, p=0.008 and 0.20, 0.06-0.65 for SCT vs no SCT, p<0.001, respectively). Higher LV mass and lower RV TAPSE were associated with increased odds of having >5% of interstitial amyloid deposition on biopsy in the multivariable logistic regression analysis (OR 5.5, 95% CI 1.1-26.8 for >195.6g vs ≤195.6g, p=0.036 and 8.1, 1.2-54.3 for RV TAPSE<1.6cm vs ≥1.6cm, p=0.032, respectively).

Conclusions:
LA GLS
<
13.5 was an independent predictor of mortality in our cohort, and its performance in the routine assessment of AL amyloidosis may be justified. Furthermore, SCT for cardiac AL amyloidosis was associated with improved OS. This finding needs to be confirmed by larger studies in the era of contemporary systemic therapies. Although LV mass and RV TAPSE were associated with higher interstitial amyloid deposition, histopathologic parameters did not predict mortality in this cohort.
Abstract 12025: Fatty Acid-Binding Proteins Promote Pulmonary Arterial Hypertension via Upregulation of Endothelial Glycolysis
Authors: Liu Bin , Li Shuai , Yi Dan , Pan Jiakai , Ramirez Karina , Vanderpool Rebecca , Rafikov Ruslan , Gu Haiwei , Fallon Michael , Dai Zhiyu
Published: June 2023

Introduction:
Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients.

Hypothesis:
We hypothesis that endothelial fatty acid metabolism is critical for obstructive vascular remodeling in the pathogenesis of PAH.

Methods:
A severe mouse model of PH

Egln1
Tie2Cre

mice were bred with

Fabp45
-/-

mice to generate

Egln1
Tie2Cre

/

Fabp45
-/-

mice. Single-cell RNA sequencing (scRNA-seq) analysis and metabolomic analysis were used to profile the pulmonary cells in

Egln1
Tie2Cre

mice and

Egln1
Tie2Cre

/

Fabp45
-/-

mice. Human hPAEC from idiopathic PAH patients and healthy donors, monocrotaline (MCT)-induced and Sugen5416/hypoxia (SuHx)-induced PH rats were used to measure fatty acid-binding protein 4 and 5 (FABP4 and FABP5) expression. siRNA mediated knockdown of FABP4 and FABP5 and lentivirus mediated FABP4 and 5 overexpression were performed to study cell proliferation, apoptosis, glycolysis, fatty acid oxidation. Echocardiography, hemodynamics, histological and immunostaining assay were performed to evaluate the PH phenotypes.

Results:
Both FABP4 and 5 were highly induced in the ECs of

Egln1
Tie2Cre

mice and PAECs from IPAH patients, as well as the whole lungs of MCT and SuHx-induced PH rats. Knockdown or overexpression of FABP4-5 reduced or enhanced EC proliferation, starvation-induced Caspase 3/7 activity, glycolysis and fatty acid oxidation. Genetic deletion of
Fabp4
and 5 in

Egln1
Tie2Cre

mice exhibited a reduction of right ventricular systolic pressure (RVSP), RV hypertrophy, and attenuation of pulmonary vascular remodeling, prevention of right heart failure. Fabp4-5 deletion also normalized EC glycolysis gene programming, reduced HIF-2a expression and endothelial proliferation in

Egln1
Tie2Cre

mice.

Conclusions:
FABP4 and 5 control EC glycolysis and contribute to the development of severe PH.
Abstract 12029: The Impact of the Myocardial Bridge on Coronary Functional Test in Patients With Ischemia With Non-Obstructive Coronary Arteries
Authors: Teragawa Hiroki , Oshita Chikage , Uchimura Yuko
Published: June 2023

Introduction:
The possibility of myocardial bridge (MB) causing chest pain has been widely reported; however, the effect of MBs on coronary microvessels has not been thoroughly investigated.

Hypothesis:
Thus, this study evaluated the effects of MB on epicardial coronary artery and coronary microvascular function during coronary angiography (CAG) and coronary function tests (CFT) in patients with ischemia with non-obstructive coronary arteries (INOCA).

Methods:
This study included 57 patients with INOCA who underwent CAG and CFT to evaluate chest pain. In CFT, acetylcholine was first administered intracoronarily in a stepwise manner, followed by chest symptoms, electrocardiographic changes [Editor1] and CAG. Positive coronary spasm was defined as coronary vasoconstriction of >90% on CAG accompanied by chest symptoms or electrocardiographic ST-T changes. After nitroglycerin administration, CAG was performed to assess MB, which is defined as the systolic narrowing of the coronary artery diameter by >20% compared to that in diastole. Coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were subsequently obtained by transvenous adenosine triphosphate infusion using a pressure wire. Coronary microvascular vasodilatory dysfunction (CMD) was defined as CFR of <2.0 or IMR of ≥25 units.

Results:
Of the 57 patients, 13 (23%) had MB. The CAG and coronary CFT results in the MB (+) and MB (–) groups are shown below.

Conclusions:
These findings suggest that MB predisposes to coronary spasms in patients with INOCA. Conversely, MBs may have a limited effect on microvessels, particularly in such patients.
Abstract 12047: miR-148-3p:mdfic Pathway Improves the Efficacy of Therapeutic Cardiac Reprogramming
Authors: Sun Hualing , Pratt Richard E , dzau victor , Hodgkinson Conrad
Published: June 2023

We, and others, have demonstrated that directly reprogramming scar fibroblasts into new cardiomyocytes improves cardiac function in the infarcted heart. A major challenge is the relatively low conversion rate of fibroblasts into cardiomyocytes. We pioneered reprogramming method based on miRNAs, whereby fibroblasts were converted into cardiomyocytes via combination of four miRNAs which we called miR combo. We hypothesized that the efficacy of miR combo could be improved via additional miRNAs. To that end, we screened a number of miRNAs and found that miR-148-3p significantly enhanced the efficacy of miR combo with respect to the expression of cardiomyocyte genes (Actn2, Myh6 and Tnni3; 2 to 5 fold; N=5; P<0.05). Validating a role for miR-148a-3p, addition of the anti-miR-148a-3p inhibited the ability of miR-148a-3p to enhance reprogramming efficacy (N=5, P<0.05). In silico analysis, miR-148a-3p transfection studies, and luciferase reporter assays indicated that Pten, Pik3r3, Rock1 and Mdfic were miR-148a-3p targets. Of these targets, only the overexpression of Mdfic inhibited miR combo (N=4, P<0.05). In contrast, siRNA-mediated knockdown of Mdfic enhanced miR combo efficacy (Actn2, Myh6 and Tnni3; 2 to 10 fold; N=3; P<0.05). These studies suggested that Mdfic was a repressor of the cardiomyocyte phenotype. To provide further evidence, Mdfic mRNA levels were measured in freshly isolated cardiomyocytes and fibroblasts. Mdfic was found to be virtually absent in cardiomyocytes and strongly expressed in fibroblasts (N=3, P<0.05). Moreover, ChIP-qPCR and co-immunoprecipitation analysis indicated that in fibroblasts, Mdfic resided solely on cardiomyocyte genes where it inhibited gene expression by preventing the binding of transcription activator proteins (N=3, P<0.05). In summary, miR-148a-3p improves the efficacy of fibroblast to cardiomyocyte reprogramming via the down-regulation of Mdfic.
Abstract 12086: Predicting Long-Term Survival After De Novo Cardioverter-Defibrillator Implantation for Primary Prevention
Authors: Wang Chang ( , Lu Zihang , Simpson Chris , Lee Douglas S , Tranmer Joan E
Published: June 2023

Introduction:
Current guidelines recommend the use of implantable cardioverter-defibrillators (ICDs) for primary prevention of arrhythmia in patients with reduced ejection fraction cardiomyopathy. Little is known about the long-term outcomes of patients with ICDs in clinical practice.

Objective:
To develop a risk prediction model for 10-year survival after ICD implantation for primary prevention.

Methods:
In this population-based registry of all ICD patients across 18 centers in Ontario, CA, 5097 patients receiving ICD implant for primary prevention from February 2007 to March 2011 were followed for up to 10 years. Patients were randomly split 2:1 into derivation and internal validation cohorts to develop and validate a prognostic model using Cox regression and predictors measured at initial ICD evaluation.

Results:
Mean age was 65.3 years (SD 11.0), 664 patients were female (19.5%) and 2344 patients (69.0%) had ischemic cardiomyopathy for primary disease indication. 10-year survival was 45.7% (95% CI 44.0%-47.4%).The final prediction model included age, sex, disease indication, comorbidities and biomarkers at the time of ICD assessment (
Table 1
). This model had good discrimination in derivation (AUC 0.80; 95% CI 0.78-0.81) and validation samples (0.79, 95% CI 0.77-0.81) and good calibration. Sensitivity analyses showed that the addition of device type, provider factors (implantation site, implanter volume, physician main specialty), sex-related interaction terms, and frailty scores did not significantly improve the prediction model.

Conclusion:
A combination of demographic and patient factors determined at baseline device evaluation enabled the prediction of 10-year survival in patients undergoing ICD for primary prevention in the clinical practice. Our findings may help identify and monitor individuals at risk of long-term mortality and may be useful in targeting future prevention strategies to enhance longevity in this high-risk population.
Abstract 12109: Cardiac LDLR Drives Chimeric SARS-CoV-2-Induced Myocarditis in K18 hACE2tg Mice
Authors: Condor Capcha Jose Manuel , Iansen Irion Camila , Saad Ali , Lambert Guerline , Wong Amanda , Villano Jason , Pekosz Andrew , Ranek Mark J , Shehadeh Lina A
Published: June 2023

Introduction:
Cardiovascular disease patients with COVID-19 present prolonged hospitalization and increased mortality. Cardiovascular complications including myocarditis have been reported in association with COVID-19. We recently reported that levels of cardiac low-density lipoprotein receptor (LDLR) are elevated in patients with heart failure. We hypothesized that LDLR may play a role in COVID-19-induced myocarditis.

Methods:
K18 h
ACE2
tg mice were inoculated with SARS-CoV-2 Washington (WA-1) native strain, replication-competent chimeric (ch) SARS-CoV-2, or PBS and lung viral load and histopathology were compared (N=4). We interrogated the LDLR in 4-month-old K18 h
ACE2
tg mice via intravenous injection of AAV9-cTnT-hLDLR (gain of function), AAV9-cTnT-hIDOL (Induced Degrader of LDLR, loss of function), or AAV9-cTnT-Luciferase (control). After 4 weeks, mice were inoculated intratracheally with chSARS-CoV-2. Five days after inoculation, mice were sacrificed, and blood and tissues collected for histopathological analysis and RNA/protein studies to evaluate myocarditis. Myocarditis was established by histological analysis according to the Dallas criteria.

Results:
Both native SARS-CoV-2 and chSARS-CoV-2 had ~60% infectivity as measured by qPCR and immunostaining. Over-expression (OE) of cardiomyocyte-specific hLDLR together with chSARS-CoV-2 induced myocarditis with prominent cardiomyocyte degeneration, necrosis, and immune cell infiltration: T cells (59 cells/mm
2
;p<0.05) and Macrophages (109 cells/mm
2
;p=0.0002) compared to the single control groups. In addition, hLDLR-OE increased heart expression of Osteopontin (12.6 vs 1.2%;p<0.05), pAKT(Ser473) (14.4 vs 3.5; p<0.05) and ICAM-1 (9.0 vs 3.3%; p<0.05). OE of cardiac-specific hIDOL mice infected with chSARS-CoV-2 reduced macrophage infiltration into the heart compared to hLDLR-OE myocarditis and control chSARS-CoV-2 groups (p<0.0001 and p<0.05), respectively. hIDOL-OE reduced cardiac ICAM-1 compared to myocarditis and control chSARS-CoV-2 groups (p<0.01 and p<0.05), respectively.

Conclusions:
Cardiac LDLR drives COVID-19-associated myocarditis in a new mouse model of SARS-CoV-2 infection.