bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13319: Subclinical Atherosclerosis in American Indian Adolescents and Young Adults and the Risk of Fatal and Non-Fatal Cardiovascular Events: The Strong Heart Family Study (SHFS)
Authors: Reese Jessica A , Roman Mary J , Deen Jason , Ali Tauqeer , Cole Shelley , Devereux Richard B , Fretts Amanda M , Howard Barbara , Lee Elisa T , Malloy Kimberly , SINGH Parmanand , Umans Jason G , Zhang Ying
Published: April 2022

Introduction:
Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Subclinical atherosclerosis is typically detected later in life and may develop into clinical CVD. Although investigators have established the association in older adults, the burden of subclinical atherosclerosis and its relation to CVD risk among AI youth is unclear.

Hypothesis:
Subclinical atherosclerosis will be prevalent and the risk of CVD will be higher in AI with atherosclerotic plaque in adolescence and early adulthood.

Methods:
We evaluated AI participants from the SHFS, who were 14-39 years old, CVD free, and had a carotid ultrasound at the baseline examination, 2001-2003 (n=1,376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified fatal and/or non-fatal CVD events through the end of 2019 with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between subclinical atherosclerosis and time to CVD events, while controlling for covariates.

Results:
Among 1,376 participants, 71 (5.2%) had atherosclerotic plaque at baseline. During follow-up, 120 (8.7%) participants had a fatal or non-fatal CVD event. CVD incidence was higher in participants with baseline plaque (13.51/1,000 person-years) than in those without (4.95/1,000 person-years, p=0.0003, Figure 1). Risk of CVD was higher in participants with baseline plaque compared to those without, while controlling for age and obesity (CVD HR=1.85, 95% CI=1.02-3.37, p=0.0420).

Conclusions:
AI adolescents and young adults have an unexpectedly high prevalence of atherosclerotic plaque, which is independently associated with incident CVD later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.
Abstract 13322: Development of the Preclinical Science Integration and Translation (PRESCIANT) Method and Application to the Apolipoprotein E Knockout Mouse Atherosclerosis Model
Authors: Shuey Megan M , Xiang Rachel R , Moss Mary , Carvajal Brigett V , Wang Yihua , Camarda Nicholas , Fabbri Daniel , Rahman Protiva , Ramsey Jacob , Stepanian Alec , Sebastiani Paola , Wells Quinn , Beckman Joshua A , Jaffe Iris Z
Published: April 2022

Introduction:
Animal models of human diseases are used extensively to interrogate molecular mechanisms in a reductionist fashion. We tested whether aggregation and integration of preclinical data can identify new causative pathways that faithfully model human disease mechanisms. We have termed this novel technique, the Preclinical Science Integration and Translation (PRESCIANT) method.

Methods and Results:
Data were extracted from 716 manuscripts in the journal Arteriosclerosis, Thrombosis, and Vascular Biology from 1995-2019 using the apolipoprotein E knockout mouse (ApoE-KO) to study atherosclerosis. We identified 360 unique studies in which genes were experimentally perturbed in ApoE-KO mice to impact atherosclerotic plaque size and/or composition. Impacts of the interventions on plaque size, inflammation, and lipid content were analyzed using Ingenuity Pathway Analysis. The top upstream regulatory network (sc-58125, a COX2 inhibitor) linked 37.2% (134) of the genes implicated in atherosclerosis into a single network. Further, Ingenuity Pathway Analysis identified TREM1 signaling, LXR/RXR activation, and renin-angiotensin signaling as the top 3 pathways associated with changes in atherosclerosis parameters. Specifically, early atherogenesis genes were enriched with pathways associated with inflammatory cell migration and infiltration (including TREM1) whereas late atherosclerosis genes were associated with cell metabolism and survival (including LXR/RXR activation). These two pathways were interrogated in a clinical cohort of 88,660 patients by testing for association between genetically predicted expression of the human homologs of mouse pathway genes and a composite phenotype composed of 27 human atherosclerosis diagnoses. There was a significant enrichment (p<0.01 for both pathways) in the number of human homologs associated with atherosclerosis, including 12 (57.2%) genes in the TREM1 pathway and 15 (53.6%) in the LXR/RXR pathway.

Conclusion:
PRESCIANT can successfully leverage decades of animal investigations to translate results from large-volume singular preclinical studies to make novel causal inferences into human disease.
Abstract 13328: Effect of Atrial Fibrillation on Patient-Reported Outcomes in Heart Failure and Preserved Ejection Fraction: Secondary Analysis of Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial
Authors: Elkholey Khaled , Whyte Seabrook , Asad Zain Ul Abideen , THADANI Udho , Stavrakis Stavros
Published: April 2022

Introduction:
Atrial fibrillation (AF) and heart failure (HF) both significantly impact morbidity and mortality, and also account for impaired quality of life. Patient-reported outcomes represent the most direct measurement of quality of life, without influence of interpretation by the clinician. We sought to evaluate the effect of AF on patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with HF with preserved ejection fraction (HFpEF) enrolled in TOPCAT trial.

Methods:
This was an exploratory post-hoc analysis of the TOPCAT trial. Patients with reported KCCQ at randomization were included in this analysis. KCCQ was collected at randomization, 4, 12, 24, 36, 48, and 72 months. Mixed model repeated measure ANOVA was used to explore the effect of AF status at the time of randomization on longitudinal changes in the KCCQ- overall symptom score (OSS) over the duration of follow-up. Covariates adjusted for included age, gender, race, diabetes mellitus, history of HF hospitalization and use of ACEIs or ARBs.

Results:
A total of 3403 patients (mean age 68.5±9.5 years, females 51.5%) with available KCCQ-OSS at baseline were included. AF was prevalent in 1202 (35.3%) patients at baseline (mean age 71.0±9.3, 46.3% women, 91.7% white). AF patients had higher prevalence of stroke, diabetes mellitus, hypertension and lower prevalence of HF hospitalization. Over the duration of follow-up, there was a significant time by AF status interaction (p<0.001), suggesting that KCC-OSS changed differently overtime based on the AF status.

Conclusions:
Among patients with HFpEF from TOPCAT cohort, prevalent AF at baseline was associated with lower quality of life and lower KCCQ-OSS over 5 years of follow-up, suggested by the significant interaction between AF status and time of follow-up.
Abstract 13335: Elevated Protease Inhibitor SERPINA3 is Associated With Increased Mortality and Improves Prognostic Stratification in a
de novo
or Worsened Heart Failure
Authors: Delrue Leen , Vanderheyden Marc , Beles Monika , Dierckx Riet , verstreken sofie , Heggermont Ward , Bartunek Jozef
Published: April 2022

Introduction:
Overexpression of serpin peptidase inhibitor, clade A member 3 (SERPINA3) has been associated with poor prognosis in cancer.

Hypothesis:
SERPINA3 in
a de novo
or worsened heart failure (HF) bears a prognostic information alone and in addition to established biomarkers NT-proBNP and ST2 or clinical risk factors.

Methods:
Circulating SERPINA3 levels were examined in HFpatients who died within 5 years (n=44) and compared with age- and hemodynamically matched survivors (n=39). Prognostic value of circulating SERPINA3 levels alone and in combination with ST2 and NT-proBNP was then analyzed in an independent cohort with a de novo or worsened HF (n=384).

Results:
Plasma SERPINA3 levels were significantly higher in HF non-survivors compared to survivors (334.7 ± 138.7 vs 228.2 ± 83.1 μg/mL, p<0.01). In the spline curve analysis,SERPINA3 level of 316 μg/mL emerged as optimal cut-off value for mortality. In the validation cohort with a
de novo
or worsened HF (n=384), circulating SERPINA3 levels >316 μg/mL were associated with increased all-cause mortality (HR (95% CI): 2.4 (1.5-3.9), p=0.0002) and its composite with unplanned cardiac admission (HR (95% CI): 2.0 (1.2-3.3), p=0.004). In a multivariate analysis, including established clinical risk factors and ST2 and NT-proBNP, SERPINA3 remained independent predictor of all-cause mortality together with age, ST2, glomerular filtration and pulmonary capillary wedge pressure.

Conclusions:
Elevated SERPINA3 appears to provide additional prognostic information in models incorporating clinical, hemodynamic and laboratory risk including ST2 and NT-proBNP by identifying a subgroup of heart failure patients at increased mortality risk.
Abstract 13349: Circulating Factors Promote Metabolic Remodeling and Mitochondrial Dysfunction in Single Ventricle Congenital Heart Disease
Authors: Garcia Anastacia M , Pires Da Silva Julie , Baybayon-Grandgeorge Angela , A Miyano Carissa A , Sparagna Genevieve C , Sucharov Carmen C , Miyamoto Shelley
Published: April 2022

Introduction:
While heart failure (HF) remains a leading cause of death and indication for transplant in single ventricle heart disease (SV) patients, the molecular mechanisms associated with the progression to HF are poorly understood. The purpose of this study is to investigate if serum circulating factors from failing SV patients remodel cardiomyocyte metabolism, as is seen in the failing SV heart. Additionally, we investigated the effect of sildenafil on cardiomyocyte metabolism
in vitro.

Methods:
We used a novel
in vitro
model that consists of primary cardiomyocytes (NRVMs) treated with serum from failing SV patients (SVHF) or bi-ventricular non-failing (BVNF) controls, +/- sildenafil. Mass spectroscopy was used to quantitate mitochondrial cardiolipin and investigate the metabolite composition of serum-treated NRVMs. Mitochondrial respiration was assessed using the Seahorse Bioanalyzer (Agilent), and reactive oxygen species (ROS) were quantified using the Amplex Red (Thermo Fisher). Enzyme and gene expression were analyzed using RT-qPCR and western blot, and relative mtDNA copy numbers were determined by qPCR.

Results:
While relative mitochondrial copy number was not significantly altered, failing SV serum decreases NRVM mitochondrial function (Fig. 1A-C), which is associated with decreased mitochondrial cardiolipin, increased reactive oxygen species (Fig. 1D), and altered expression of enzymes implicated in lipid and metabolic remodeling. Importantly, many of these changes are abrogated by sildenafil (Fig 1A-D).

Conclusions:
Together these data suggest that SV serum circulating factors promote lipid and metabolic remodeling in cardiomyocytes and that mitochondria represent a novel therapeutic target of sildenafil in the failing SV heart. Elucidation of the molecular mechanisms involved in modulation of cardiac energy metabolism in SV will be important to improve cardiac function and enhance transplant-free SV survival.
Abstract 13350: Pulmonary Embolism Readmission Trend Over the Years: A National Readmission Database Study
Authors: Shaka Hafeez , Velagapudi Sujitha , Murthi Mukunthan , Marcos-Abdala Hernan G. M , Atluri Ramtej , Velazquez Genaro R
Published: April 2022

Introduction:
Acute pulmonary embolism(PE) is known to be associated with significant short term and long term complications. However with evolution of PE management, the outcomes of PE related complications and need for readmission has not been well studied. Our aim of this study is to see the trend in readmissions in PE patients from the years 2010 to 2018.

Methods:
We utilized the National Readmission Database from 2010 to 2018 to identify hospitalized patients with a principal diagnosis of acute pulmonary embolism. Identified the total number of readmissions for acute PE from 2010 to 2018. Multivariate cox regression model was used to identify independent predictors of readmission.

Results:
The number of patients with 30-day readmissions have gradually increased from 14,508 in 2010 to 19,703 in 2018. The proportion of females admitted was higher than males in all years.The 30-day all cause readmission after principal admission for PE decreased from 11.2% to 9.7% from 2010 to 2014 but increased to 11.8% in 2018 (p<0.001). Risk adjusted readmission specific for PE showed a decrease from 1.2 to 1% (p=0.023) from 2010 to 2018, with the proportion decreasing from 11.9% to 9.5% during the same period. There was no significant difference in the inpatient mortality (p=0.382) and length of stay (p=0.658) during the study period. There was an increasing trend in the total hospital charges from 2010 (13,374$) to 2018 (15,104$) but the difference was not statistically different (p=0.086).

Conclusion:
Our study suggests that there is a statistically significant decrease in PE specific readmission, with a decrease followed by an increase in all-cause admission after a PE. There is also no significant difference in mortality and length of stay. These findings warrant further studies to elucidate the mechanism for decrease PE-specific readmission but possible causes for the increase in all-cause readmission in the hope of optimizing management and continuing improving outcomes.
Abstract 13366: Cardiovascular Risk Profile of Middle Eastern Immigrants Living in the United States
Authors: Yahya Tamer , Acquah Isaac , Hagan Kobina , Javed Zulqarnain , Taha Mohamad , Valero Elizondo Javier , Al-Mallah Mouaz , Chamsi Pasha Mohammed , Faza Nadeen N , Zoghbi William A , Cainzos Achirica Miguel , Nasir Khurram
Published: April 2022

Introduction:
Middle Eastern (ME) immigrants are one of the fastest-growing groups in the US. Several studies have noted a relatively high burden of CVD in ME countries. In the US, while their risk profile has been partially described as part of immigrant studies, the burden of risk factors and ASCVD have not been studied in detail among ME immigrants.

Methods:
We used 2012-2018 data from the National Health Interview Survey (NHIS), a US nationally representative survey. ME origin was ascertained through self-reported region of birth. ASCVD and CVD risk factors were also self-reported. We compared these to US-born non-Hispanic white (NHW) individuals in the US, using chi-square tests and logistic regression models.

Results:
Among 139,778 adults included, 886 (representing 1.3 million individuals, mean age 46.8) were of ME origin, and 138,892 were US-born NHWs (representing 150 million US adults, mean age 49.3). ME participants were more likely to have higher education, lower income and be uninsured. The age-adjusted prevalence of hypertension (22.7% vs 27.8%) and obesity (22.1% vs 32%) were significantly lower in MEs vs NHWs participants, respectively. There were no significant differences between the groups in the age-adjusted prevalence of ASCVD, diabetes, hyperlipidemia, and smoking. Only physical inactivity was higher among ME individuals
(Fig)
. In multivariable analyses, ME participants had lower odds of hypertension (OR 0.71, 95% CI 0.61, 0.83) and obesity (OR 0.61, 95% CI 0.52, 0.72), and higher odds of physical inactivity (OR 1.30, 95% CI 1.11, 1.53), with no significant differences in the other factors or ASCVD
(Fig)
.

Conclusions:
ME immigrants in the US exhibit a more favourable cardiovascular risk profile compared to NHWs. Further studies are needed to determine whether this finding is related to lower risk, selection of a healthier ME subgroup in NHIS, or possible under-detection of cardiovascular risk factors in ME immigrants living in the US.
Abstract 13373: Cost-Effectiveness of Population-Based Atrial Fibrillation Screening Using Wearable Devices
Authors: Chen Wanyi , Khurshid Shaan , Singer Daniel , Atlas Steven , Ashburner Jeffrey M , Ellinor Patrick T , McManus David D , Chhatwal Jagpreet , Lubitz Steven A
Published: April 2022

Introduction:
Screening of atrial fibrillation (AF) using contemporary wrist-worn wearable devices may prevent strokes, but false positive diagnoses could also lead to unnecessary bleeding and utilization of healthcare resources.

Aim:
To assess the cost-effectiveness of contemporary AF screening strategies and identify optimal conditions for the deployment of such strategies.

Methods:
We developed a microsimulation model to evaluate 8 distinct AF screening strategies, including 6 strategies utilizing wrist-worn wearable devices and 2 strategies utilizing traditional modalities (
Figure
). Within a simulated cohort of 30 million individuals with an age, sex, and comorbidity profile matching the US population aged ≥65 years (i.e., with a guideline-based screening indication), we assessed cost-effectiveness from the healthcare system perspective using incremental cost-effectiveness ratios (ICERs) at a willingness-to-pay of $100,000 per quality-adjusted life-year (QALY). We used scenario analyses to identify conditions under which the cost-effectiveness of screening may be optimized.

Results:
In the base case analysis, 7/8 strategies were effective (87.5%, range of QALYs gained 14-862 per 100,000 people). All 6 contemporary screening strategies were effective (range of QALYs gained 226-957 per 100,000 people). The most cost-effective strategy was wearable photoplethysmography, followed conditionally by wearable electrocardiogram with patch monitor confirmation (ICER $57,882/QALY, Figure). The cost-effectiveness of screening was consistent across multiple scenarios, including across strata of sex and targeting the US population aged ≥50 years.

Conclusions:
AF screening utilizing wrist-worn wearable devices appears cost-effective, and merits prioritization by potential payers.
Abstract 13386: Extracellular Matrix Signaling in Marfan Syndrome Induced Pluripotent Stem Cell Derived Smooth Muscle Cells
Authors: Dalal Alex R , Pedroza Albert J , Yokoyama Nobu , Nakamura Ken , Shad Rohan , Fischbein Michael P
Published: April 2022

Introduction:
Mutation in the extracellular matrix (ECM) protein
fibrillin-1
lead to aortic root aneurysm in Marfan Syndrome (MFS). ECM composition influences vascular smooth muscle cell (SMC) phenotype, contractility, and signaling through mechanotransduction. Induced pluripotent stem cell-derived SMCs (iPSC-SMCs) are emerging as an attractive approach to model patient-specific vascular disease, but the use of iPSC-SMCs to investigate extracellular matrix biology remains limited.

Hypothesis:
Diseased MFS ECM induces phenotype modulation in healthy Control cells, while Control ECM will rescue contractile phenotype in MFS.

Methods:
Label-free mass spectroscopy core matrisome proteomic profiling of MFS and Control iPSC-SMCs from ammonia hydroxide decellularized ECM was performed. Decellularized ECMs were repopulated with MFS or Control iPSC-SMCs (N=3) (Figure A) and RNA extracted from whole cell lysate for RNA sequencing after four days of culture.

Results:
24 core matrisome proteins were differentially expressed including overexpressed Collagen 1A1 and Tenascin C in MFS and enriched Thrombospondin 1 and Latent TGF-β Binding Protein 2 in Control (Figure B). Control iPSC-SMCs dramatically decreased contractile gene expression (
ACTA2
and
CNN1
) and ECM synthesis (
COL1A1
and
FN1
) when cultured on the diseased MFS ECM compared to the native Control ECM (Figure C). Conversely, the MFS cells expressed equally low contractile genes and the synthetic phenotype was exacerbated when cultured on the Control ECM (Figure D).

Conclusions:
Control iPSC-SMC mechanotransduction remains intact when interacting with the MFS ECM resulting in phenotype modulation into a MFS-like cell. Irreversible reprogramming of the MFS iPSC-SMC prevents rescue of the contractile phenotype when grown on a healthy ECM, despite the absence of MFS specific matrisome proteins. The decellularized iPSC-SMC ECM system effectively captures cell-ECM interactions and signaling.
Abstract 13418: Sociodemographic Disparities in Neighborhood Social Cohesion Among Adults With Atherosclerotic Cardiovascular Disease in the United States
Authors: Mszar Reed , Grandhi Gowtham R , Osei Albert D , Mahajan Shiwani , Valero Elizondo Javier , Javed Zulqarnain , Sharma Garima , Blaha Michael J , Mossialos Elias , Al-Kindi Sadeer , Hyder Adnan , Cainzos-Achirica Miguel , Nasir Khurram
Published: April 2022

Introduction:
Social environment and neighborhood factors, including perceived social cohesion, represent key determinants of health. While evidence has shown that low cohesion may be adversely associated with cardiovascular health and higher levels may be cardioprotective, few studies have assessed the association between cohesion and sociodemographic factors among adults with atherosclerotic cardiovascular disease (ASCVD).

Methods:
Using a U.S. nationally representative sample (National Health Interview Survey [NHIS], 2013-18), we examined the association between sociodemographic characteristics and neighborhood social cohesion in adults with ASCVD. Social cohesion was categorized based on the sum of the four subscales: 1) people in this neighborhood help each other out; 2) there are people I can count on; 3) people can be trusted; and 4) this is a close-knit neighborhood. The composite score was then split at or above and below the median.

Results:
Among 17,017 NHIS participants with ASCVD (representing 18.3 million adults annually), 8,988 (54%) reported low neighborhood social cohesion, corresponding to 9.9 million adults. A higher proportion of those aged 18-39 years (71%), non-Hispanic Black (67%) and Hispanic (68%) individuals, uninsured (71%) adults, and immigrants (65%) reported low social cohesion compared to other groups. In multivariable logistic regression, those aged 18-39 years and 40-64 years, non-Hispanic Black and Hispanic adults, individuals with a low-income, and immigrants had increased odds of low social cohesion (Figure). Overall, 80% of adults with 4 of these characteristics had low social cohesion.

Conclusion:
Sociodemographic factors are associated with disparities in neighborhood social cohesion among adults with ASCVD. Future studies should assess the causal relationship between social determinants and neighborhood cohesion, the consequences of low social cohesion, and potential approaches to ameliorate it.
Abstract 13420: Machine Learning for Risk Stratification in Pulmonary Arterial Hypertension - Can It Achieve the Gold Standard?
Authors: Scott Jacqueline M , Kanwar Manreet , Liu Zilu , Lin Shili , Antaki James , Perer Adam , Benza Raymond L
Published: April 2022

Background:
Pulmonary arterial hypertension (PAH) is a fatal and difficult to treat disease due to patient inter-variability. Accurate risk stratification is necessary for guiding treatment but no PAH risk calculator has achieved "excellent performance" (receiver-operator AUC > 0.8). Conversion of REVEAL 2.0 to a Bayesian network has shown promising results (Pulmonary Hypertension Outcomes Risk Assessment or PHORA). In this study, a new Bayesian network model (PHORA 2.0) was developed with a novel network structure and optimal feature selection.

Methods:
Patient-level data had been previously aggregated and harmonized across six PAH clinical trials (AMBITION, PATENT-1/2, GRIPHON, SERAPHIN, FREEDOM-EV, ARIES-1/2); all patients were assessed at baseline. Forty-one variables were initially considered based on p-value ranking from previous meta-analyses, availability across trials, and expert opinion. Training data was created by random sampling of 80% of the harmonized dataset, dropping early censored patients (N = 2531), leaving 20% of the data as a test set (N = 626). Continuous variables were discretized through univariate decision trees using 10-fold cross-validation maximizing Brier score. Genetic search selected combinations of features that maximized ranked correlation (Kendall’s tau) with one-year survival, with increasing penalty for redundant features. Feature combinations were evaluated in augmented naïve Bayesian networks, the best model was selected by 10-fold cross-validation on training data. Final performance is reported as performance on the test set.

Results:
The final model achieved the best cross-validation AUC using 16 variables. Performance on the test set was an AUC = 0.85. The final model outperformed multiple risk calculators at test time (Figure 1).

Conclusion:
Bayesian network modeling coupled with genetic feature selection has discovered for the first time a one-year mortality model for PAH with excellent performance.
Abstract 13429: Intercalated Disk Nanoscale Structure and Ion Channel Distribution Regulate Cardiac Conduction
Authors: Moise Nicolae , Struckman Heather , Veeraraghavan Rengasayee , Weinberg Seth
Published: April 2022

The intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+ channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains such as the gap junction-adjacent perinexus and mechanical junction-associated adhesion-excitability nodes, and that perturbations of ID structure, such as those that appear in disease states like heart failure or atrial fibrillation, alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, no systematic investigation of how ID nanostructure influences cardiac conduction in health or disease has yet been done. Based on our previously published work, we develop an approach to integrate the distribution of ion channels within the ID and ID nanoscale structure in a realistic finite element model, based on experimental measurements from transmission electron microscopy (TEM) and stochastic optical reconstruction microscopy (STORM) images. Tissue-scale simulations demonstrated that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we find that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of post-junctional Na+ currents. Further, we find that disruption of local ID nanodomains can lead to either conduction slowing or enhancing, depending on gap junctional coupling strength. Overall, our study demonstrates that ID nanoscale structure and ion channel distribution can play a significant role in regulating cardiac conduction.
Abstract 13431: Gain-of-Function Mutations in RNA Binding Motif 20 Result in Cardiac Remodelling and Pathogenesis in Mice
Authors: Zhang Yanghai , Wang Chunyan , Methawasin Mei , Braz Camila U , Gao-Hu Jeffrey , Yang Betty , Strom Joshua , Hacker Timothy A , Khatib Hasan , Granzier Henk L , Guo Wei
Published: April 2022

Gain-of-function mutations of a gene result in new molecular function. Genetic studies show that mutations in a gene named as RNA binding motif 20 (RBM20) are associated with dilated cardiomyopathy (DCM). To test whether Rbm20 mutations are responsible for cardiac remodelling and potential underlying mechanisms, we selected two mutations (S637A and S639G) located in arginine/serine-rich domain of RBM20 and generated two knock-in mouse models (

Rbm20
S637A

and

Rbm20
S639G

) respectively. Both mouse lines were subjected to histological and anatomical analysis as well as cardiac function assessment with echocardiography. The results revealed that heterozygous (HT) and homozygous (HM) male and female mice from both lines displayed DCM phenotype with enlarged left ventricular (LV) chamber, thinner LV walls and reduced ejection fraction. Interestingly, we observed that

Rbm20
S639G

mice manifested more severe phenotype than that in

Rbm20
S637A

mice.

Rbm20
S639G

HM mice exhibited higher mortality rate (~50%) than that (~34%) in

Rbm20
S637A

HM mice at an early age (<100 days). Differentially expressed and spliced genes from RNA-seq data are involved in arrhythmia, cardiomyopathy, and sudden death based on Human Phenotype Ontology enrichment analysis (FDR≤0.05) in both lines. Immunofluorescent analysis in tissues and single cardiomyocytes respectively showed both mutations promote RBM20 nucleocytoplasmic trafficking and protein condensates, suggesting they are gain-of-function mutations, leading to high mortality rate at younger age. Both mutations also interrupted the alternative splicing of
TTN
and calcium handling genes. Force measurements and Ca
2+
transient evaluation of intact myocytes showed that the reduced cellular diastolic stiffness and impaired contractility in HT and HM mice. Studies suggested that phosphorylation of RS domain is critical for protein trafficking. We then performed mass spectrometry on the
in vitro
expressed RBM20 and identified phosphorylation on S637 and S639. Phosphomimetic assay showed that phosphorylation was not responsible for RBM20 trafficking and condensates. Together, we reported a new mechanism by which cardiac genetic mutations causes protein trafficking and aggregation in cardiac remodelling.
Abstract 13433: Enhancing Autophagic Flux Maintains Mitochondrial Homeostasis in Cardiac Ischemia/Reperfusion Injury
Authors: He Lihao , Yang Jing , Chu Yuxin , He Jin , Hua Yutao , Chen Yunxi , Ballinger Scott W , Young Martin E , Prabhu Sumanth , Xie Min
Published: April 2022

Introduction and Hypothesis:
Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. Similarly, augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective by reducing infarct ~50% and improved systolic function. TB increases autophagic flux and reduced reactive oxygen species (ROS) in the infarct border zone, which is abolished in ATG7 KO mice. We will test whether TB cleans damaged mitochondria and induces mitochondrial biogenesis during cardiac I/R injury.

Methods:
8-12-week-old, wild-type, C57BL6 mice were randomized into two groups: TB and Tat-Scrambled (TS) control peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Mitochondrial abundance, quality, and dynamics were assayed. In addition, cultured adult mouse ventricular myocytes (AMVMs) from conditional cardiomyocyte ATG7 knockout (ATG7 KO) and control mice, and neonatal rat ventricular myocytes (NRVMs) treated with ATG7 and control siRNA were used to evaluate the role of autophagy.

Results:
TB increased mitochondria DNA (mtDNA) content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by ~40%, decreased ROS, and increased mtDNA content significantly by ~50%. TB also increased the intact mtDNA significantly. Moreover, TB promoted the expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts
Drp1, Fis1,
and
MFN1
/
2.
Conversely, ATG7 knockdown in NRVMs and cardiomyocyte-specific ATG7 KO in myocardium abolished the beneficial effects of TB on mtDNA content. To test the changes in the myocardium are cardiomyocyte-specific, we verified the effects of TB and the loss of ATG7 in isolated AMVMs.

Conclusions:
Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce I/R injury in myocardial infarction.
Abstract 13442: Renin-Angiotensin Metabolite Profiling via LC-MS/MS Reveals Sex Dependent Differences Induced by High-Salt Diet in Dahl-S Rats
Authors: Dube Prabhatchandra R , Mohammed Chrysan J , Khalaf Fatimah , Zhang Shungang , Faleel Dhilhani , Soehnlen Sophia , Connolly Jacob , Kleinhenz Andrew , Domenig Oliver , Dworkin Lance , Malhotra Deepak , Haller Steven , Kennedy David J
Published: April 2022

Background:
Understanding how sex influences the pathophysiology of cardiovascular and renal disease may enhance precision medicine approaches that account for sex specific biologic differences in these diseases. Nevertheless, characterization of preclinical models often fail to account for the role of sex on important pathophysiologic mechanisms. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development and progression of cardiovascular and renal disease. In addition to the classic RAAS pathway, an alternative RAAS pathway produces angiotensins (e.g. Ang [1-7]) that can counteract classical RAAS hormones such as Angiotensin (Ang) II. We hypothesized that RAAS profiling in a high-salt fed Dahl-S rat model would reveal significant sex differences in both classic and alternative RAAS pathways.

Methods/Results:
Ten week-old male and female Dahl-S rats were fed either 0.2% salt normal chow (SS-NC), or 8% high-salt diet (SS-HS) for eight weeks (n=6-8/group). Equilibrium RAAS profiling via LC-MS/MS was performed in lithium heparin plasma samples. In response to high-salt diet, both male and female SS-HS rats had significant (p<0.05) reductions vs. their respective SS-NC controls in plasma aldosterone (-93% in male SS-HS, -97% in female SS-HS), Ang II (-71% in male SS-HS, -41% in female SS-HS), Ang IV (-79% in male SS-HS, -54% in female SS-HS) as well as calculated plasma renin activity (-67% in male SS-HS, -42% in female SS-HS), although the magnitude of reduction was generally greater in males vs. females. Alternatively, only male SS-HS rats had significant (p<0.05 vs. SS-NC) reductions in plasma Ang I (-63%), Ang III (-66%), as well RAAS metabolites of the alternative RAS axis, Ang [1-5] (-58%) and Ang [1-7] (-70%) vs. SS-NC. Comparing female vs. male SS-HS rats, females had significantly (p<0.01 vs. male) increased levels of angiotensins of the classic RAS pathway, such as Ang I (113%), Ang II (104%), Ang III (150%) and Ang IV (265%) after high-salt diet.

Conclusion:
High-salt diet induces significant sex-dependent differences in both classic and alternative RAAS pathways of Dahl-S rats and may provide important insight into the sex-dependent differences of cardiovascular and renal injury seen in this model.
Abstract 13443: Multi-Center Independent Validation of an Automated Algorithm for Predicting Cardiorespiratory Deterioration Events in Single Ventricle Patients
Authors: Rusin Craig G , Acosta Sebastian , Vu Eric , Brady Ken , Scahill Carly , Fonseca Brian , Barrett Cindy , Simsic Janet , Yates Andrew R , Klepczynski Brenna , Gaynor J W , Penny Dan J
Published: April 2022

Introduction:
Sudden acute deterioration is common in patients with hypoplastic left heart syndrome and comparable lesions. Previous work by the investigators using a single-center cohort at Texas Children’s Hospital (TCH) resulted in a novel algorithm which can predict such events 1-2 hours in advance.

Hypothesis:
The TCH algorithm for predicting deterioration events in single ventricle patients 1-2 hours in advance can be translated to heart centers across the country without significant performance loss.

Methods:
A prospective study on infants undergoing cardiovascular surgical palliation at Children’s Colorado, Nationwide Children’s Hospital, and Children’s Hospital of Philadelphia between Oct 2018 to Apr 2020 was conducted. Subjects were admitted to the cardiovascular ICU (CVICU) immediately after stage-1 palliation and enrollment continued until stage-2 palliation was performed or the subject was discharged. All physiologic data from all subjects were recorded from bedside monitoring equipment using the Sickbay system (Medical Informatics Corp, Houston, TX) in both CVICU and step-down units. Instances of cardiorespiratory deterioration, defined as the need for CPR or endotracheal intubation, were identified. The existing predictive algorithm was applied without re-training to the data obtained from study sites. A 12-hour lead-in period was used to initialize the algorithm. The ROC area, true and false positive rates (TRP & FPR) were used to quantify performance.

Results:
There were 58 subjects who met inclusion criteria across all sites. Median time between stage I & II surgeries was 141 days (126-155 IQR). A total of 30 in-hospital deterioration events were observed. Twenty-one subjects experienced at least 1 event. Most (72%) events occurred 40 days after stage I surgery. Over 29K hours of data was collected from subjects. The ROC area was found to be 0.927 for predicting deterioration events 1-2 hours in advance of overt extremis.

Conclusions:
This study validated the performance of an existing predictive algorithm which provides a 1-2 hour early warning for cardiorespiratory deterioration events in children with single ventricle physiology during their interstage period using a large, independent, multi-center patient cohort.
Abstract 13446: Rapid Eye Movement Sleep is Associated With Ambulatory Blood Pressure in Hypertension
Authors: Vungarala Soumya , sompalli sreeja , Singh Prachi , Danyluk Alexandria B , Kuniyoshi Fatima H , Somers Virend K , Covassin Naima
Published: April 2022

Introduction:
Growing evidence suggests that aberrant sleep architecture is linked to heightened risk of cardiovascular disease independently of sleep apnea. Rapid Eye Movement (REM) sleep is characterized by increased sympathetic activity and blood pressure (BP) compared to non-REM sleep stages. However, whether REM sleep is associated with BP across the 24 hours has not been investigated.

Hypothesis:
We hypothesized that increased REM sleep would be associated with higher ambulatory BP.

Methods:
We recruited 137 individuals (58% men, aged 39±14 years, office systolic/diastolic BP [SBP/DBP] 125±14/77±11 mmHg) who completed overnight polysomnography followed by 24-h ambulatory BP monitoring. Sleep was scored according to standard criteria. 24-h, daytime, and nighttime averages were calculated for SBP, DBP and heart rate. REM sleep duration was computed as percentage of total sleep time and used to group participants into tertiles as follows: T1 (REM% ≤18.8), T2 (REM% 18.9-24), and T3 (REM% ≥24.1).

Results:
Sex ratio, body mass index, and apnea-hypopnea index were similar across REM tertiles, but age increased with increasing tertiles (p=0.029). 24-h SBP (T1 vs T2 vs T3: 121±12 vs 117±7 vs 124±12 mmHg, p=0.015) and DBP (72±7 vs 70±6 vs 76±8 mmHg, p<0.001) differed across REM sleep tertiles, with significantly higher values in those in the highest tertile. Results were consistent when considering daytime SBP (T1 vs T2 vs T3: 126±12 vs 122±8 vs 132±14 mmHg, p<0.001) and DBP (77±7 vs 76±6 vs 83±9 mmHg, p<0.001), and nighttime DBP (65±9 vs 61±7 vs 65±8 mmHg, p=0.047). No differences were noted on nighttime SBP or any heart rate measures. A significant interaction was found between hypertension status and REM sleep in multiple regression analysis, with the observed associations being significant only among hypertensives (n=69). In those with hypertension, REM sleep duration was associated with 24-h mean BP independently of age, sex, body mass index, apnea-hypopnea index and antihypertensive medications (standardized beta 0.22, p=0.041).

Conclusions:
Longer REM sleep duration is independently associated with elevated ambulatory BP in individuals with hypertension. REM sleep may be a novel cardiovascular risk indicator in this population.
Abstract 13457: Renin-Angiotensin System Inhibitor Exerts Prognostic Effect in HFpEF Patients With Low Chloride Level
Authors: Shirotani Shota , Jujo Kentaro , Kishihara Makoto , Watanabe Shonosuke , Endo Nana , Takada Takuma , Abe Takuro , Minami Yuichiro , Nobuhisa Hagiwara
Published: April 2022

Background:
Hypochloremia is associated with a poor prognosis of heart failure (HF) patients. Serum chloride level is known to be affected by serum renin secretion; however, this relationship is one of the least investigated field in HF patients. Renin-angiotensin system inhibitor (RASi) is recommended as a first-line medication for HF patients with reduced left ventricular ejection fraction (LVEF), but its prognostic effect is still controversial in HF patients with preserved EF (HFpEF).

Hypothesis:
The prognostic benefit of RASi depends on the baseline serum chloride level in HFpEF patients.

Methods:
This observational study included 1,913 consecutive patients who admitted to hospital due to worsening of HF and discharged alive. After excluding patients who received regular hemodialysis and those whose LVEF <50%, 506 HFpEF patients were ultimately analyzed. They were divided into two groups by serum chloride levels at admission (Low-Chloride group: -101 mEq/L; High-Chloride group: 102- mEq/L), referred to prior reports. Death from any cause as the primary endpoint was compared between patients who received RASi at discharge and those who did not, in each chloride group.

Results:
During the observation period with 479 days of median follow-up, 77 (15%) died. Patients who received RASi had significantly lower mortality than those who did not, only in the Low-Chloride group (Log-rank: p=0.001,
Figure
). In the multivariate Cox regression analysis with diverse covariates, the rate of risk reduction by RASi for the mortality was greater in patients in the Low-Chloride group than High-Chloride group (HR: 0.35 and 0.71, respectively). The prognostic advantages of RASi were evident in patients with low chloride level, but not in those with high chloride level at admission (P for interaction=0.027).

Conclusion:
In this observational study, the administration of RASi was associated with an improved prognosis of HFpEF patients only in low serum chloride level at admission.
Abstract 13467: Using Data Analytics Toward Precision Warfarin Dosing in Children With Heart Disease
Authors: Algaze Claudia , Vesey Annie , Mak Kwai , Algaze Claudia , Collins Ronnie T
Published: April 2022

Introduction:
Warfarin is the most common anticoagulant used in children with heart disease. Multiple factors make initial warfarin dose selection and management subjective and variable in children. This variability increases hospital length of stay and impacts efficacy and safety. We sought to develop a data-driven tool to optimize time to warfarin goal dose in children with heart disease.

Methods:
We collected all demographic and clinical data for all patients <18 years who received warfarin at our institution. We developed a warfarin sensitivity metric (Δ International Normalized Ratio (INR)/mg warfarin) to assess individual medication processing and characterize influential factors. Each inpatient interaction with warfarin was analyzed to assess the impact of concomitant medications, hepatic impairment, and procedure type on dosing, sensitivity, and resultant INR. A linear regression model was formulated to predict ending warfarin dose based on these influential factors.

Results:
A total of 714 patients were identified; 334 patients met inclusion criteria, and 447 unique encounters with warfarin were analyzed. Warfarin sensitivity was 94.3% higher in patients receiving major anticoagulation enhancing drugs and 13.6% higher in patients with minor liver injury. Patients undergoing a Fontan procedure had increased warfarin sensitivity compared to other procedures; 60% and 66% increase from ventricular assist device and valve replacement, respectively. A linear regression model was used to predict a patient’s warfarin ed dose based on age, baseline INR, other medications, liver injury, and Fontan procedure status. The Fontan binary indicator and age were the most impactful in predicting end dose with an adjusted R
2
of 0.1792.

Conclusions:
We have identified multiple factors that could affect individualized warfarin. Further analysis will refine our warfarin sensitivity metric and finalize and validate our tool to allow accurate and efficient warfarin dose prediction.
Abstract 13470: Update on Lipid Profiles and Lipid Modifying Therapies in Heart Transplant Recipients, a Single Center Experience
Authors: Cao Lin , Schlendorf Kelly , Zalawadiya Sandip , Huang Shi , Harrell Frank , Lindenfeld Joann , Song Wen-Liang
Published: April 2022

Introduction:
Statin use after heart transplant (HT) has been shown to reduce rates of CAV and improve morbidity and mortality regardless of lipid profile. However, drug-drug interactions (DDIs) between statins and immunosuppressive therapies limit their use, particularly at higher doses. Recently, non-statin lipid modifying therapies have also been used in the HT population, despite a lack of outcome trials.

Objective:
We sought to examine current trends in lipid profiles and lipid-lowering therapy use in the HT population.

Methods:
We performed a retrospective chart review of 198 HT recipients (average age 53.6 years, 139 males, 59 females) transplanted between 4/8/2016 and 3/24/2020 at a single center. Of those patients, 82 underwent HT for ischemic cardiomyopathy (ICM), and 116 underwent HT for nonischemic cardiomyopathy (NICM). Lipid panels and medications were collected pre-transplant, immediately post-transplant, and 1-year post-transplant. Most recent values were also collected. At each point the 2018 lipid guidelines were used to determine the recommended intensity of statin each patient should ideally be on if they were not transplant patients.

Results:
Median cholesterol, triglyceride, HDL, and LDL values were reasonably well-controlled post HT. Despite high overall rates of statin use, our data suggest that most HT recipients are on lower than guideline-recommended statin doses due to DDI, particularly in the ICM group. The proportion of patients on non-statin lipid modifying therapies increased over time.

Conclusions:
There is emerging evidence that non-statin therapies added to statins can further reduce atherothrombotic events in non-transplant patients. These therapies may offer options for additional lipid control in transplant recipients whose statin use is limited by DDIs. However, the pathophysiology of CAV and atherosclerosis are different, and outcome trials of non-statin lipid therapies in HT patients are urgently needed.