bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13747: Undernutrition Severity Correlates With Worse Outcomes in Patients Admitted With Peripheral Artery Disease
Authors: Mohamad Alahmad Mohamad Alhoda
Published: December 2023

Introduction:
Malnutrition has been associated with inferior outcomes in general. However, there is a lack of data to assess if the degree of malnutrition correlates with worse outcomes in patients with peripheral artery disease (PAD).

Methods:
We used Nationwide Readmission Database (NRD) for 2016-2019 in our study. First, we extracted all cases older than 18 years that include a primary diagnosis of PAD. Appropriate survey and domain analyses were applied to obtain national estimates using SAS 9.4.

Results:
We identified 599,717 discharges with PAD. Malnutrition was present in 8% of the study cohort (or 49,853 cases). Half of the patients with malnutrition (or 26,090) had moderate to severe malnutrition. Malnourished patients had similar age distribution compared to those without malnutrition (mean age 71 years vs. 72 years) and slightly more women (42% vs. 37%, p<0.001). Patients with malnutrition had a higher prevalence of underlying heart failure, dementia, coagulopathy, malignancy, and chronic (liver, renal, and lung) diseases (p<0.001), but similar frequency of hypertension and diabetes. They also had significantly higher inpatient mortality (6% vs. 1.4%, p<0.001), length of stay (mean of 15 days vs. 11 days, p<0.001), and all-cause 30-day readmission rates (27% vs. 22%, p<0.001). Inpatient mortality on readmission was also higher in those with malnutrition (9% vs. 3.8%, p<0.001). Univariate analysis showed that the severity of malnutrition also correlated with higher inpatient mortality (OR 3.8[3.4-4.2] for mild malnutrition and 5[4.6-5.5] for advanced malnutrition). Figure 1 shows that malnutrition is associated with higher inpatient mortality even after adjustment for significant comorbidities and vascular interventions.

Conclusions:
In patients hospitalized with PAD, underlying malnutrition is an adverse prognosticator.
Abstract 13763: Reducing Cardiovascular Disease Risk by Estrogen Treatment After Surgical Menopause in Combination With the Suppression of Interferon Gamma Pathway in
Ldlr
Null Mice
Authors: Zhu Lin , Litts Bridget , An Julia , Rein Jeffrey , Chinnarasu Sivaprakasam , Linton Macrae F , Stafford John M
Published: December 2023

Atherosclerotic cardiovascular disease (ASCVD) risk is increased in women after menopause, which has not been shown to be reversed by postmenopausal hormone therapy. To understand the underlying mechanism for the lack of improvement in ASCVD with hormone therapy,
Ldlr
-/-
mice with established atherosclerosis were subjected to procedures of surgical menopause (ovariectomy, ovx), 17β-estradiol (E
2
) treatment after ovariectomy (ovx+E
2
), or sham. In all groups, hyperlipidemia was normalized with a chow diet. Ten weeks later, atherosclerosis burden and ASCVD risk were evaluated. Atherosclerosis was reversed by the resolution of hyperlipidemia in sham but not ovx nor ovx+E
2
mice. While E
2
treatment improved lipid management in ovx mice, we observed persistent inflammation, which presented as high levels of IFNγ, IL-6, and C-PEP2 as well as impaired HDL anti-atherogenic functions and unresolved inflammation in the atherosclerosis lesion. To further investigate the role of inflammation in persistent ASCVD during hormone therapy, the interferon gamma (IFNγ) pathway was suppressed in a second cohort of

Ldlr
-/-

mice that were constituted with bone marrow from
Ifn
γ

-/-

mice following lethal irradiation. Similar to the 1
st
cohort of mice, E
2
treatment improved ASCVD risk factors including hyperlipidemia and insulin actions. In mice carrying IFNγ
-/-
bone marrow, atherosclerosis lesion size was reversed with E
2
treatment, which was associated with decreased IFNγ and IL-6 in the blood. We are further investigating the HDL functions and lesion inflammation in this cohort. Our studies indicate that limiting inflammation may be needed in order to restore the cardiovascular benefits of menopause E
2
treatment.
Abstract 13767: Cardiac Reprogramming Reduces Fibrosis and Improves Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
Authors: Yamada Yu , Sadahiro Taketaro , Nakano Koji , Honda Seiichiro , Abe Yuto , Fujita Ryo , Ieda Masaki
Published: December 2023

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is a disease associated with high morbidity and mortality. Cardiac fibroblasts (CFs) contribute to HFpEF pathogenesis through interstitial/perivascular fibrosis and diastolic dysfunction; however, little is known regarding the mechanisms of the fibrosis, and therapies targeting it are lacking. Cardiac reprogramming is a promising approach for myocardial infarction by overexpressing Mef2c/Gata4/Tbx5/Hand2 (MGTH) in CFs, however, it remains undetermined whether cardiac reprogramming is effective in HFpEF.

Aims:
This study aims to determine the effectiveness of cardiac reprogramming in HFpEF.

Methods:
We generated a novel Tcf21iCre/Tomato/MGTH2A transgenic mouse system, where cardiac reprogramming can be induced in a druggable manner with lineage tracing. We first tested whether this system could improve the HFpEF mouse model. To determine the efficacy of cardiac reprogramming and the mechanisms of cardiac fibrosis in HFpEF, we performed multi-omics, including single cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and epigenome analysis. Finally, we generated mouse lines that induce each of the reprogramming factors and investigated whether overexpression of a single factor alone could improve HFpEF, which we also examined in human CF.

Results:
We found that cardiac reprogramming reduced fibrosis and improved diastolic dysfunction in HFpEF. scRNA-seq and spatial transcriptomics revealed that multiple CF clusters upregulated fibrotic profiles to induce diffuse interstitial fibrosis, whereas the distinct profibrotic CF cluster contributed to perivascular fibrosis, which were reversed with cardiac reprogramming. Mechanistically, cardiac reprogramming changed the epigenetic landscape by recruiting Gata4 to loci. Notably, overexpression of only Gata4 improved HFpEF by reducing fibrosis and suppressed profibrotic signatures in human CFs without generating cardiomyocytes.

Conclusions:
Cardiac reprogramming may be a promising approach for HFpEF via anti-fibrosis.
Abstract 13787: Restricted Coronary Flow Reserve of Mental Stress Induced Myocardial Ischemia in Angina and No Obstructive Coronary Artery Disease
Authors: ma huan , Guo Lan , Yin Han , Liu Yuting , Bai Bingqing , liu fengyao , Wang Haochen , Geng Qingshan
Published: December 2023

Background:
The myocardial blood flow (MBF) mechanism in mental stress-induced myocardial ischemia (MSIMI) in angina with no obstructive coronary artery disease (ANOCA) population is unknown.

Methods:
13-NH
3
cardiac PET-CT was utilized to assess MBF and perfusion changes under mental stress (ms) and adenosine stress (as) in ANOCA subjects and gender- and age-matched healthy controls. MSIMI was defined as an increase in perfusion defect score of ≥3 points.

Results:
Among the 126 participants enrolled, ANOCA women showed a significantly higher prevalence of MSIMI compared to the healthy controls (36/84 vs. 1/42,
p
<0.001). Perfusion defects under ms occurred synchronously however more pronounced in the left anterior descending and right coronary artery territories, consistent with a significantly higher MBF hyperemia in the left circumflex territory. MBF
ms
shows a close correlation with rate-pressure product (RPP
ms
) (
p
<0.05 in ANOCA&MSIMI+, ANOCA&MSIMI-, and control groups with r
pearson
ranging from 0.39-0.65). Although no differences existed in absolute MBF
ms
values between groups, there were notable increasing trends among the three groups in corrected MBF, which reflected blood flow supply-demand balance (ANOCA&MSIMI+: 0.96±0.23 vs. control group: 1.10±0.29,
p
=0.020), and in coronary flow reserve (CFR) (ANOCA&MSIMI+: 2.41±0.75 vs. control group: 2.89±0.77,
p
=0.016). Furthermore, after adjusting for confounding factors, only subjects in ANOCA&MSIMI+ group did not exhibit a corresponding increase in MBF
ms
matching MBF
as
.

Conclusion:
Restricted CFR, indicating impaired coronary microvascular function, and mismatch between myocardial blood supply and demand together constitute the pathogenic mechanism of MSIMI in ANOCA population. More researches are still needed in exploring the brain-heart interaction in MSIMI.
Abstract 13790: Efficacy of Stellate Ganglion Block for Refractory Ventricular Arrhythmias: An Updated Systematic Review
Authors: Yeo Yong Hao , Tan Min Choon , Tham Jia Wei , Lee Justin , Rattanawong Pattara
Published: December 2023

Background:
Stellate ganglion block (SGB) has emerged as an alternative approach to refractory ventricular arrhythmias (VAs). However, data on the outcome of SGB for refractory VAs are limited.

Objective:
This study aimed to assess the in-hospital efficacy of SGB in refractory VAs.

Method:
A systematic search was performed in MEDLINE and EMBASE according to the PRISMA guidelines from July 2017 to October 2022. Studies reporting the characteristics of in-hospital VAs before and after the SGB were included. Studies that had missing outcomes were excluded.

Results:
Of 515 publications reviewed, 162 patients (60.6 ± 13.6 years of age, 81.5% male) were included across 27 studies. Amongst, 103 patients (63.6%) had ischemic cardiomyopathy, and the mean ejection fraction was 29.8 ± 12.7%. Prior to the SGB procedure, 100 patients (61.7%) required two or more anti-arrhythmic medications control. Following SGB, there was a significant 92% reduction of VAs episodes from 13.9 ± 18.5 to 0.9 ± 2.1 (p<0.01) during the hospitalization (31±35 days). Of the reported patients, 46.5% remained free of VAs, and 53.5% had recurrences before discharge. Among 61 patients who required additional neuromodulation after SGB in the same hospitalization, 32 patients (52.5%) received repeated SGB, 15 patients (24.6%) underwent surgical sympathectomy, and 14 patients (23%) underwent catheter ablation. Of the reported patients, 75.4% of patients survived throughout the hospital course.

Conclusion:
SGB significantly reduced VAs episodes in patients with refractory VAs during hospitalization. More than three-quarters of the patients survived following the SGB for refractory VAs. This highlights the potential effective role of SGB in managing refractory VAs.

Figure
Change in Ventricular Arrhythmias Burden after Stellate Ganglion Block
Abstract 13795: Reduced Fetuin-A Levels Are Associated With Exercise Intolerance in Patients With Heart Failure and Predict the Risk of Adverse Outcomes
Authors: Tomita Yusuke , Misaka Tomofumi , Sugawara Yukiko , Anzai Fumiya , Sato Yu , Kimishima Yusuke , Yokokawa Tetsuro , Sato Takamasa , Oikawa Masayoshi , Kobayashi Atsushi , Yoshihisa Akiomi , Takeishi Yasuchika
Published: December 2023

Background:
Impaired exercise tolerance is a feature of heart failure (HF) and predicts adverse outcomes in patients with HF. Hepatokines are proteins synthesized and secreted by the liver, which regulate systemic metabolisms of peripheral tissues. However, the clinical impact of hepatokines on exercise capacity has not been well understood.

Aims:
Our objective was to investigate the relevance of a hepatokine, Fetuin-A, in relation to exercise capacity in HF.

Methods and Results:
We conducted a prospective study involving 120 consecutive hospitalized patients (mean 57.3 years old, 75.0% male) with HF who underwent cardiopulmonary exercise testing. The serum concentration of Fetuin-A was measured by an enzyme-linked immunosorbent assay. Patients with impaired exercise tolerance (peak oxygen uptake (VO
2
) < 14.0 mL/kg/m) exhibited lower Fetuin-A levels than those without (
Figure A
). Correlation analysis revealed that Fetuin-A was positively correlated with peak VO
2
and negatively correlated with minute ventilation to carbon dioxide production ratio and its slope. We then followed up patients and found 12 composites of cardiac events that included 5 cardiac death and 7 worsening HF. Based on classification and regression tree to determine the cut-off of Fetuin-A, Kaplan-Meier analysis revealed that patients with lower Fetuin-A levels (< 22.2 ng/mL) and impaired exercise tolerance had the highest risk of cardiac events (
Figure B
). In a multivariable Cox proportional hazard model, the presence of both lower Fetuin-A and exercise intolerance was independently associated with an increased risk of cardiac events (hazard ratio, 18.8; P = 0.009).

Conclusions:
Reduced Fetuin-A levels were associated with exercise intolerance in patients with HF, and those with decreased levels of both Fetuin-A and peak VO
2
were at the highest risk of adverse outcomes.
Abstract 13805: Associations of Subclavian Artery Calcification With Future Cardiovascular Events and Death: The Multi-Ethnic Study of Atherosclerosis
Authors: Duprez Daniel A , Jacobs David R , Daniels Michael R , Andrews Leah , Brumbach Lyndia , Denenberg Julie , Watanabe Kelly , Cornelissen Guillaume Germaine , Criqui Michael H , Szklo Moyses , Allison Matthew A
Published: December 2023

Introduction:
Atherosclerosis affects the upper limbs and may be a marker of diffuse atherosclerosis and increased risk for cardiovascular events.

Hypothesis:
Subclavian artery calcification (SAC) and thoracic aorta calcification (TAC) obtained by chest CT provide additional information about future CV events and death beyond coronary artery calcification (CAC) and CV risk factors.

Methods:
Chest CT scans of MESA participants (N = 2519) at exam 5 (2016-18) were interrogated for the presence and extent of SAC, TAC, and CAC. Proportional hazards regression was conducted for associations with incident total CVD events (n = 209), adjusted for age, race/ethnicity, and sex, then SAC, TAC, and CAC adjusted for demographics and each other, and finally adding adjustment for CV risk factors.

Results:
The mean age of the sample was 68.3±9.2 years; 48% were male, 27% Black, 13% Chinese, 22% Hispanic, 38% White. The prevalence of any calcification was 62% for SAC, while being 60 and 69% for TAC and CAC, respectively. Among those with any calcification, N and median Agatston score were SAC: 1704, 76; TAC: 1655, 152; CAC 1896, 135. CAC predicted future events in all models (Table). After adjustment for demographics, the ln(Agatston score +1) in each calcified vascular bed predicted future CVD. Mean±SD of the predictors were ln(SAC+1): 2.4±2.4, ln(TAC+1) 2.7±2.9 and ln(CAC+1) 3.1±2.6. SAC, but not TAC, was still predictive after mutual adjustment. SAC was marginally predictive (HR: 1.08, p = 0.06) when CV risk factors were also included in the model.

Conclusions:
Calcification was common in all 3 vascular beds, but there is no evidence that predictions using SAC and TAC are independent of CAC. We speculate that although the tendency to calcify is similar across vascular beds, CAC is most relevant for incident CVD.
Abstract 13909: It’s All About the Fat: Most Subjects With Metabolically Obese Normal Weight Have Either High Body Fat or Central Obesity
Authors: chen zhuo , Li Jingen , Medina-Inojosa Betsy , Medina-Inojosa Jose R , Lara-Breitinger Kyla , Somers Virend K , Acosta Andres , Lerman Amir , Lopez-Jimenez Francisco
Published: December 2023

Introduction:
Metabolically obese normal weight (MONW) refers to metabolic abnormalities despite normal body mass index (BMI).

Hypothesis:
Because obesity is generally defined by BMI, it is assumed that people with MONW do not have excessive adiposity but still have the metabolic dysregulation associated with adiposity.

Methods:
We included participants aged 20-65 of the National Health and Nutrition Examination Surveys from 1999-2006 and 2011-2018 with normal BMI (18.5-25 kg/m
2
), fasting blood samples, and DEXA data. According to the AHA criteria, MONW was defined having ≥3 of the following criteria, besides a normal BMI: Hypertriglyceridemia (≥ 150 mg/dL) or treatment for elevated triglycerides; HDL cholesterol level < 40 mg/dL in men or <50 mg/dL in women or treatment for reduced HDL-C; elevated blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg) or antihypertensive treatment or history of hypertension; elevated fasting plasma glucose ≥ 100 mg/dL or insulin/oral hypoglycemic treatment and central obesity by waist circumference (≥ 94 cm in men and ≥ 80 cm in women). High fat percentage was defined as ≥25% in men, ≥35% in women. Weighted logistic regression was performed to test the relation between MONW and high fat%, central obesity.

Results:
Of the 7,887 participants (53.6% men; mean age±SE was 39.23±0.24 years), 2433 (33.4%) had normal BMI included in the analysis. Among these, 148 had MONW (5%). Mean Fat% was 26.08±0.36% in those with MONW versus 21.90±0.17% in those without MONW for men, and 37.02±0.35% versus 33.31±0.21% for women. MONW subjects were 2.21 times more likely to have either central obesity or high fat % (OR 12.09, 95%CI: 6.18-23.67, p<0.01) and 2.18 times more likely to have high fat % (OR=2.84, 95%CI: 1.72-4.67, p<0.01) (see Figure).

Conclusions:
Most individuals with MONW have either increased fat content, central deposition of fat, or both. That highlights people with normal BMI may still have metabolic complications of adiposity.
Abstract 13952: Neurodevelopmental Outcomes in Early Adolescence: The Pediatric Heart Network’s Single Ventricle Reconstruction Trial
Authors: Miller Thomas , Trachtenberg Felicia , Sharma Binu , Goldberg Caren S , Newburger Jane W , Panigrahy Ashok , Gongwer Russell , Gaynor J W , Kral Mary , Sananes Renee , Shah Amee , Tsang Rocky , Gustafson Kathryn , Lambert Linda M , Votava-Smith Jodie , Heinrich Kimberley , ilardi dawn
Published: December 2023

Introduction:
Neurodevelopmental (ND) and functional impairments for survivors of palliated hypoplastic left heart syndrome (HLHS) are among the most consequential morbidities, resulting in an increased risk of poor school performance and lower reported quality of life. Longitudinal follow-up of those enrolled in the Single Ventricle Reconstruction (SVR) III study provides opportunity to measure important outcomes such as ND, and understand associated risk factors.

Goals/Aims:
Describe and identify predictors of ND outcomes at 10-12 years of age in participants enrolled in SVR.

Methods:
Transplant-free survivors from the SVR III trial were invited to complete in-person ND assessments, including the Wechsler Intelligence Scale for Children-V, Wechsler Individual Achievement Test-III, and the Behavior Rating Inventory of Executive Function (BRIEF). Descriptive and regression analyses were performed.

Results:
Of the 237 enrolled in SVR III, 200 (84%) received a ND assessment. Participants who did vs did not undergo assessment were more likely to be male (63% vs 51%), white (87% vs 76%) and have a higher Child Opportunity Index (61 ±26 vs 46 ±39). Mean Full Scale IQ for the cohort was almost 1 standard deviation (SD) below the normative mean (88 ±18), with 39% >1 and 15% >2 SD below the normative mean. Similar patterns were seen for Reading (38% >1 SD and 16% > 2SD) and Math Composites (38% >1 SD, 19% > 2SD). Executive functions measured with the BRIEF were similarly affected, with 25% to 45% of individuals showing clinically significant (T score >65) Plan/Organization problems on parent and teacher forms, respectively. Measures of socioeconomic status, number of complications, and requirement for a gastrostomy-tube were all independent predictors for multiple ND outcomes.

Conclusions:
In early adolescence, transplant-free survivors of surgical palliation for HLHS show clinically significant ND concerns across multiple domains of functioning. The distribution of outcomes is broad. Our findings support the American Heart Association recommendations for screening and evaluation in middle school to inform interventions that promote academic success and quality of life.
Abstract 13959: A Role for Striated Muscle Nuclear Receptor Co-Regulator RIP140 (
Nrip1
) in the Control of Endurance Fitness
Authors: Pruzinsky Elizabeth K , Yamamoto Tsunehisa , Batmanov Kirill , Khurana Tejvir , Kelly Daniel P
Published: December 2023

During the development of heart failure (HF), the capacity for myocardial fatty acid oxidation (FAO) and oxidative phosphorylation is reduced, leading to an energy-starved state. Similar metabolic derangements occur in skeletal muscle during HF and with physical inactivity associated with chronic disease states. Receptor Interacting Protein 140 (RIP140) is a nuclear receptor co-regulator that has been shown to repress the transcription of genes involved in mitochondrial energy transduction in highly metabolic tissues. We recently demonstrated that striated muscle-specific RIP140 KO mice (str-RIP140
-/-
) were protected against the development of HF and had an adaptive form of cardiac hypertrophy (PMID: 36927960). To assess the impact of RIP140 deficiency on skeletal muscle function, we conducted physiological and genomic interrogation of str-RIP140
-/-
mice. We found that the str-RIP140
-/-
mice display an endurance performance phenotype. Specifically, str-RIP140
-/-
mice run significantly longer on an endurance treadmill regimen (str-RIP140
-/-
= 118.0 min, WT= 73.38 min; p= <0.0001) with increased VO
2max
compared to controls (str-RIP140
-/-
= 9779 ml/kg/hr, WT= 7748 ml/kg/hr; p= <0.0001). Respiratory Exchange Ratio (RER) was maintained at a decreased level during exercise in str-RIP140
-/-
mice vs controls, indicative of increased utilization and capacity for FAO. The response of str-RIP140
-/-
mice to endurance exercise training was also assessed. str-RIP140
-/-
mice achieved a greater VO
2max
following 8 weeks of training compared to control trained mice (str-RIP140
-/-
= 9589 ml/kg/hr, WT= 8366 ml/kg/hr; p= 0.002). RNA-sequence analysis comparing RIP140
-/-
and control fast-twitch muscle (EDL) prior to and following exercise training identified differentially upregulated genes involved in an array of pathways activated with endurance training including mitochondrial FAO, triglyceride turnover, the slow-twitch fiber program, angiogenesis, and components of the neuromuscular junction. We conclude that RIP140 serves as a co-repressor of a network of genes involved in skeletal muscle endurance. These results suggest that RIP140 could prove to be a target for novel metabolic therapies aimed at cardiac and skeletal muscle diseases.
Abstract 13971: Gender Differences in Advanced Heart Failure Characteristics and Outcomes
Authors: Farooqui Naba , Killian Jill , Smith Jamie , Redfield Margaret M , Dunlay Shannon M
Published: December 2023

Introduction:
The epidemiology and pathophysiology of heart failure (HF) differs in women and men. However, it is not well defined whether these differences extend to the subgroup of patients that develop advanced HF or if they translate to differences in outcomes.

Aim:
To compare the clinical characteristics and outcomes of advanced HF in women and men.

Methods:
This is a retrospective cohort study of all adult residents of Olmsted County, Minnesota with advanced HF (as defined by European Society of Cardiology Criteria) from 2007-2017. Differences in survival and hospitalization risks following advanced HF development in women and men were examined using Cox proportional hazard regression and Andersen Gill models, respectively.

Results:
Of 936 individuals with advanced HF, 417 (44.6%) were women and 519 (55.4%) were men. Women were older (mean 79 vs 75 years) with a lower overall comorbidity burden (Charlson comorbidity index 4.7 vs 5.2), less often had coronary artery disease (60% vs 79%) and hyperlipidemia (69% vs 77%), but more often had hypertension (91% vs 87%) and depression (32% vs 24%), and more often had advanced HF with preserved ejection fraction (60% vs. 30%) compared with men (
p<0.05
for each). After adjustment for age, ejection fraction and comorbidities, there were no differences in risks of survival or hospitalizations (
Figure
) between women and men (p> 0.10 for each).

Conclusion:
While advanced HF can occur in both women and men, their phenotypes differ; women more often present with advanced HFpEF and men with more atherosclerotic disease and advanced HFrEF. Despite these differences, survival is similar in women and men with advanced HF.
Abstract 13987: RBX1-CRLs Are Essential for Perinatal Heart Development by Regulating Hippo-YAP Signaling
Authors: Zambrano-Carrasco Josue , Wang Wenjuan , Ayala Juan , Sibley John , Carruth Jessica , Jiao Kai , SUN YI , Li Jie , Su Huabo
Published: December 2023

Defects in cardiac development can lead to congenital heart diseases (CHD) or predispose the heart to cardiomyopathies in adult life. The molecular mechanisms that regulate this process remain elusive. Cullin-RING E3 ligases (CRLs) are multi-subunit complexes that are critical to maintain protein homeostasis by targeting a variety of protein substrates for proteasomal degradation. In the CRLs, RBX1 serves as the catalytic subunit that promotes the transfer of ubiquitin to the target protein. Previous animal studies uncovered a crucial role for RBX1 in development. However, its importance in the developing heart has not been explored. Here, we report for the first time the indispensable role of RBX1 in perinatal cardiac development. We created mice with cardiac-specific deletion of RBX1 driven by αMHC
Cre
. Compared with littermate control mice, RBX1-deficient mouse embryos exhibited no gross morphological abnormalities at E12.5 and E14.5, displayed peripheral edema at E16.5 indicative of heart failure, and eventually died around E18.5. Histological analysis revealed myocardial hypoplasia and a substantially thinner compact layer in E16.5 mutant hearts. This event was preceded by a remarkable decrease in cardiomyocyte proliferation and diminished nuclear localization of YAP, a powerful regulator of cardiomyocyte proliferation, at E14.5. In cultured cardiomyocytes, depletion of RBX1 inhibited proliferation and induced profound transcriptomic changes like the upregulation of cardiomyopathy-related genes. Mechanistically, RBX1 deficiency destabilized multiple CRLs and resulted in the accumulation of Hippo kinases and adaptor proteins such as SAV1, LATS1/2, and MOB1 leading to the inactivation of YAP by phosphorylation. We further demonstrated that RBX1 degrades the Hippo adaptors SAV1 and MOB1. Collectively, we propose that the fine-tuned, RBX1-mediated removal of Hippo components serves as a critical checkpoint to activate YAP signaling ensuring cardiac ventricular chamber development and morphogenesis.
Abstract 14004: Geographic and Racial Variation in Oral Anticoagulant Treatment Among Commercially Insured Patients With Non-Valvular Atrial Fibrillation in the United States
Authors: Atwater Brett D , Singh Risho , Parmar Shashi , Ogbonnaya Augustina , Kang Amiee , Russ Cristina , Cheng Dong , Hagan Melissa , Deeba Serina , Hines Dionne M , Atreja Nipun
Published: December 2023

Background:
Oral anticoagulants (OACs) are recommended for non-valvular atrial fibrillation (NVAF) patients with high stroke risk. Guidelines endorse the use of direct oral anticoagulants (DOACs) over warfarin. Limited data exist on geographic variation in OAC use in the United States (US), particularly by race.

Aim:
To describe OAC utilization patterns among commercially insured NVAF patients with high stroke risk by geographic region and race.

Methods:
NVAF patients ≥18 years were identified from January 1, 2016, to August 31, 2021, in the Komodo claims database, which represents ≥140 million patients enrolled in US commercial health plans. Patients with ≥12 months of enrollment before and after NVAF diagnosis and with high stroke risk (defined as CHA

2

DS

2

-VASc Score ≥2) were included for analysis. Patients with other valvular diagnoses and/or procedures or pregnancy were excluded. Patients were classified based on treatment status as untreated, warfarin-treated, or DOAC-treated (apixaban/edoxaban/rivaroxaban/dabigatran). Results were stratified by geographic region and race (Black, White, other/unknown) and were visualized using SAS software.

Results:
After selection criteria, 619,111 NVAF patients with high stroke risk were identified with a mean age of 71 years. Over 50% of patients were untreated after NVAF diagnosis, and the untreated rate was highest in the South and West US regions. Additionally, the untreated rate was higher among Black patients than White patients (55% vs 49%, respectively). Of the treated, the overall rate of DOAC and warfarin use was 85% and 15%, respectively, with the highest rates observed in the Northeast for DOAC and Midwest for warfarin. DOAC use was lower among Black patients compared to White patients
(Figure 1)
.

Conclusion:
Among NVAF patients with high stroke risk, there are geographic and racial differences in OAC utilization that highlight areas of unmet need and opportunity for further research on these disparities.
Abstract 14007: Decreased Perceived Social Support and Heart Rate Variability Are Associated With Hopelessness in Patients With Ischemic Heart Disease
Authors: Goodyke Madison , Bronas Ulf G , Baynard Tracy , Tintle Nathan , Devon Holli A , Collins Eileen G , Dunn Susan L
Published: December 2023

Introduction:
Hopelessness is present in up to 52% of patients with ischemic heart disease (IHD) and associated with a 3.4 times increased risk of death and adverse outcomes. Decreased perceived social support (PSS) has been associated with hopelessness in patients with IHD reporting moderate-severe hopelessness but has not been examined in a well-powered sample with varying levels of hopelessness. Increased PSS is associated with increased high frequency (HF) heart rate variability (HRV) in adults following a stressful event, but the relationship between HRV and hopelessness has not been examined in patients with IHD.

Hypothesis:
The purpose of this research was to test the hypotheses that 1) lower PSS would be associated with higher hopelessness, and 2) lower HF HRV would be associated with higher hopelessness.

Methods:
Utilizing a cross-sectional design, 178 participants were enrolled while hospitalized for an IHD event at one large hospital in the Midwestern United States. Data collection occurred two weeks after hospital discharge using the State-Trait Hopelessness Scale, ENRICHD Social Support Inventory, Patient Health Questionnaire-9, a demographic form, and a short-term HRV measurement at rest. Linear models were used to assess association between variables in unadjusted models and models adjusted for demographic and medical history.

Results:
Majority of participants were male (67%), married (67%), non-Hispanic white (92%), and underwent coronary artery bypass surgery (61%). There was a moderate inverse correlation between PSS and state (
r
= -0.31,
p
< 0.001) and trait (
r
= -0.28,
p
< 0.001) hopelessness in unadjusted models. The relationships remained significant in adjusted models and did not differ between groups comparing sex, type of IHD event, and marital status. There was a moderate inverse correlation between HF HRV and state hopelessness (
r
= -0.24,
p
= 0.023). Results remained significant in adjusted models and did not differ between groups comparing sex, type of IHD event, and beta-blocker prescription.

Conclusions:
There were significant inverse associations between PSS and hopelessness and HF HRV and hopelessness. Persons with low PSS and/or HF HRV may be at greater risk for experiencing hopelessness following an IHD event.
Abstract 14022: N-terminal Prohormone of B-type Natriuretic Peptide Levels Partly Mediate the Relationship of Advanced Hepatic Fibrosis With Mortality in Coronary Artery Disease
Authors: jain vardhmaan , Mehta Anurag , Lee Terence , Liu Chang , Chew Nicholas W , Ko Yi-An , Siddiqui Mohammad , Gold Matthew , Gold Daniel A , Vatsa Nishant , Desai Shivang , . Shalimar , Fudim Marat , Pandey Ambarish , Arora Pankaj , Bugianesi Elisabetta , Sperling Laurence , Sanyal Arun , Quyyumi Arshed A
Published: December 2023

Background
Advanced hepatic fibrosis (AHF) is associated with cardiac remodeling and adverse outcomes in patients with coronary artery disease (CAD). The mechanistic basis of this relationship and the contribution of the natriuretic peptide system is unclear.

Hypothesis:
The association of AHF with mortality in CAD is mediated by circulating N-terminal prohormone of B-type natriuretic peptide (NTproBNP) level.

Methods:
Patients undergoing cardiac catheterization for evaluation of CAD were enrolled in the Emory Cardiovascular Biobank and those with acute myocardial infarction, cirrhosis, and hepatocellular carcinoma were excluded. Plasma NTproBNP was measured, and Fibrosis-4 (FIB-4) index was calculated using age, alanine aminotransferase, aspartate aminotransferase, and platelet count. FIB-4 ≥2.67 was used to define AHF. Association of AHF and NTproBNP with all-cause mortality was studied using multivariable-adjusted Cox models and mediation analyses.

Results:
Study population included 3,432 patients with mean age 65 y and among them 32% were women, 24% were Black, and 15% had AHF. Median NTproBNP level was 2.5-fold higher among those with AHF (572, 95% CI 225-2203 pg/ml) compared with those without (223, 95% CI 93-689 pg/ml). AHF was independently associated with 49% higher all-cause mortality in multivariable-adjusted Cox models [HR(95% CI): 1.49 (1.26-1.77)]. NTproBNP stratified mortality risk associated with AHF (
Figure
). Patients with AHF and high NTproBNP (≥300 pg/ml) were at the highest risk, while risk in AHF and low NTproBNP (<300 pg/ml) group was similar to those without AHF and low NTproBNP. NTproBNP was independently associated with mortality risk and mediated 61% of the effect of AHF on mortality in causal mediation analysis.

Conclusion:
NTproBNP partly mediates the excess mortality associated with AHF in patients with CAD. Therapeutic strategies targeting the natriuretic peptide system may help improve outcomes in this high-risk group.
Abstract 14093: Effects of Continuous Accelerated Pacing on Cardiac Structure and Function in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the MyPACE Randomized Clinical Trial
Authors: Wahlberg Kramer J , Infeld Margaret , Plante Tim B , Novelli Alexandra E , Habel Nicole , Barrett Trace , Meyer Markus
Published: December 2023

Introduction:
Heart failure with a preserved ejection fraction of 50% or higher (HFpEF) is prevalent and has few evidence-based therapies. In a trial of HFpEF patients with specialized pacemakers, treatment with an accelerated personalized pacing rate averaging 75 bpm (myPACE) markedly improved quality of life, NT-proBNP, physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60bpm (usual care).

Methods:
Provider-initiated echocardiographic studies obtained before and after the trial were assessed for changes in left ventricular (LV) structure and function amongst participants who continued their pacing assignment. The analytic approach aimed to detect differences in standard and advanced echocardiographic parameters within and between study arms.

Results:
Of the 100 trial participants, 16 patients in the myPACE arm and 20 in the usual care arm had a qualifying set of echocardiograms with a mean±SD time of 3.7±2.0 years apart. Heart rates were expectedly higher among myPACE patients after the trial (in bpm: myPACE 75±6 vs. usual care 65±7, p<0.001). Sustained exposure to moderately accelerated pacing resulted in a reduced septal wall thickness (myPACE 1.07±0.05mm vs usual care 1.23±0.04, p=0.008) and a lower LV mass to systolic volume ratio (myPACE 1.52±0.09 vs. usual care 1.84±0.05, p=0.038) accompanied by a small reduction in LV ejection fraction (in %: myPACE 55±1 vs usual care 60±1, p=0.015). These changes were paralleled by marked improvements in heart failure-related quality of life (MLHFQ points: myPACE 17±21 vs usual care 28±22, p<0.001). Markers of diastolic function and LV performance were not affected.

Conclusions:
Exposure to continuous accelerated pacing in HFpEF is associated with a reduced LV wall thickness and a lower mass to systolic volume ratio and ejection fraction that remained within normal limits.
Abstract 14097: State-Wise Burden of Alcohol-Induced Cardiomyopathy in the United States From 1990-2019: Results From the Global Burden of Disease Study 2019
Authors: Milutinovic Stefan , Maddineni Gautam , Rodriguez Rolando , Escarcega Ricardo O
Published: December 2023

Introduction:
Alcoholic cardiomyopathy (ACM) causes 140,000+ alcohol-related deaths yearly. Alcohol consumption and the burden of ACM vary significantly across states within the US.

Methods:
To assess the burden of ACM in the USA, we used the Global Health Data Exchange. Adult alcohol per capita consumption was obtained from the National Institute on Alcohol Abuse and Alcoholism.

Results:
Over 30 years, ACM prevalence increased by around 53.15%, reaching 198000(k). Only three US states experienced a decline in the Age-Standardized Prevalence (ASP): the District of Columbia (DC), Maryland, and Virginia. New Hampshire and Utah had the highest and lowest ASP rates, correlating with per capita alcohol consumption. Notably, total US deaths decreased by 9.7%. This decrease is primarily due to a significant reduction in female mortality by about 70%, while mortality in men continues to increase steadily. In DC, Maryland, and Hawaii, females showed the most significant improvement, with DC having the highest reduction in Age-Standardized Death Rates (ASDR) by 83%. South Dakota had the lowest ASDR for both sexes, with 25.6% and 71.88% reductions in males and females, respectively. The Age-Standardized rate of Disability-Adjusted Life Years (ASDALYs) in the US has shown a slight downward trend and has decreased to 174k. However, ASDALYs for males increased by 8.5%. DC continues to have the highest ASDALYs, but with a significant reduction (64%), while South Dakota remained the state with the lowest ASDALYs per 100k, dropping from 35.3 to 22.84.

Conclusions:
Significant disparities were observed among states, with a higher burden in males. However, these trends were not as pronounced among females, except for increased prevalence. Notably, states with higher per capita alcohol consumption showed a more significant burden of ACM. Targeted interventions aimed at high-risk populations can play a crucial role in reducing the morbidity and mortality associated with this disease.
Abstract 14128: Walking Exercise for Peripheral Artery Disease: Effects in Women and Black Americans
Authors: Whipple Mary O , Zhang Dongxue , Tian Lu , Zhao Lihui , Treat-Jacobson Diane , McDermott Mary M
Published: December 2023

Introduction:
In people with lower extremity peripheral artery disease (PAD), rates of participation in supervised exercise therapy are lower in women and Black Americans, compared to men and White Americans, respectively. This study used data from randomized clinical trials in participants with PAD to assess whether walking exercise improved walking performance in women and Black Americans.

Methods:
Data were combined from three randomized clinical trials that compared supervised treadmill exercise (3 sessions/week) for six months to a non-exercise control group. Data were also combined from two randomized clinical trials that compared home-based walking exercise for six months to a non-exercise control group. The six-minute walk (6MW), treadmill walking performance, and the Walking Impairment Questionnaire (WIQ) were measured at baseline and six-month follow-up. In meta-analyses, the effects of supervised and home-based exercise were each compared to a non-exercise control group. The effects of supervised and home-based exercise were compared directly. Tests for interaction were used to compare effects of exercise in Black, compared to White participants and in women, compared to men.

Results:
A total of 370 participants (n=159 [43%] women, n=228 [62%] Black) completed a supervised exercise trial; 349 participants (n=175 [50%] women, n=187 [54%] Black) completed a home-based exercise trial. Supervised and home-based exercise significantly improved 6MW in Black Americans and women (Table). Compared to home-based exercise, supervised exercise was associated with greater improvements in treadmill outcomes, while home-based walking improved 6MW more than supervised exercise. There was no significant interaction of sex or race on exercise outcomes.

Conclusions:
Supervised and home-based exercise significantly improved 6MW and treadmill walking distance in women and Black Americans with PAD, respectively, compared to a non-exercise control.
Abstract 14138: A Rare Encounter With Unusual Metastasis: Metastatic Right Ventricular Tumor Secondary to Cervical Cancer
Authors: Nnadi Ekendilichukwu , Khatun Nazima , Tumkur Panduranga Varshitha , john sabu
Published: December 2023

Background:
Metastasis of cervical carcinoma to the heart is a rare and uncommon phenomenon. Cervical cancer most commonly metastasizes to the lungs, liver, bones, and lymph nodes in four ways: 1) hematogenous spread, 2) lymphatic spread, 3) transvenous extension, and 4) direct extension. We present a case of a patient with cardiac metastasis from cervical cancer who initially suffered nonspecific symptoms thought to be secondary to a pulmonary embolism.

Case presentation:
A 41-year-old African American woman with a history of stage IIIB squamous cell carcinoma (SCC) of the cervix was being evaluated in the hospital for exertional dyspnea and chest pain. She was tachycardic and lung auscultation revealed decreased breath sounds bilaterally. Laboratory results were unremarkable. Initially, there was concern for pulmonary embolism (PE), computed tomography angiography with contrast demonstrated no evidence of PE but a hypoenhancing defect within the right ventricle (RV) with multiple diffuse bilateral pulmonary nodules. Echocardiography revealed RV mass vs thrombus. A cardiac MRI revealed a large infiltrative irregular mass. These findings favored evidence of a tumor rather than a thrombus. Imaging findings are illustrated in Figure 1. The patient subsequently underwent a biopsy of the right lower lobe lung nodule. The biopsy revealed metastatic SCC positive for p16, p40, and PD-L1. The patient was being treated but the prognosis was poor.

Conclusion:
Metastasis from cardiac tumors with primary cervical cancer is uncommon with a poor prognosis and average life expectancy of less than 6 months when diagnosed. Only 4% of cases of cardiac metastasis from cervical cancer are diagnosed as antemortem. A multimodality approach with prompt diagnosis is necessary for improving prognosis.
Abstract 14153: P2Y12 Inhibitors and Quality of Life Outcomes in Critically Ill Patients Hospitalized for COVID-19: A Pre-Specified Secondary Analysis of the ACTIV4a Randomized Clinical Trial
Authors: Wahid, MD Lana , Hade Erinn M , Cushman Mary , Gong Michelle N , Renard Valerie , Ko Emily R , Der Tatyana , Kornblith Lucy Z , Lawler Patrick R , Reynolds Harmony , Ahsan Chowdhury , Bochicchio Grant , Carpio Carlos , Hanna Nicholas , Hudock Kristin , Hyzy Robert , Ibanez Estellez Fatima , Iovine Nicole , Lim George , Lopez-Sendon Moreno Jose Luis , Moises Jorge , peteiro jesus , Quigley John G , WORNER FERNANDO , Kosiborod Mikhail N , Solomon Scott D , Neal Matthew D , Hochman Judith S , Berger Jeffrey S
Published: December 2023

Background:
Post-acute sequela of COVID-19 (PASC) is a complication of SARS-CoV-2 causing persistent symptoms and impaired functional status. We studied the effect of P2Y12 inhibitors on health-related Quality of Life (QoL) at 90 days in critically ill patients hospitalized for COVID-19.

Methods:
Adults hospitalized for COVID-19 who were randomized in the P2Y12 inhibitor domain of ACTIV-4a platform trial between February 2021 and June 2022. Participants were to receive usual care and either P2Y12 inhibitor (ticagrelor preferred) or no P2Y12 inhibitor for 14-days or until hospital discharge, whichever was sooner. The QoL primary outcome was determined by the EQ-5D-5L utility and visual analog scores, standardized and validated instruments. A Bayesian model estimated difference in health related QoL by randomization status adjusting for risk factors.

Results:
Among 1,502 participants, 860 critically ill patients were administered English and Spanish translations of EQ-5D-5L at 90-days. Median age was 57 years (IQR: 47, 65), 37% were female, 49% were under-represented minorities, and 10% resided in Spain. In those assigned to P2Y12 inhibitor, the mean EQ-5D-5L utility score was better in those assigned to usual care (adjusted difference: 0.08, 95% CrI: 0.03, 0.13; posterior probability of superiority [defined as a mean difference > 0] was 99.9%). Better health related QoL was also observed with assignment to P2Y12 inhibitors; EQ-5D-5L visual analog score adjusted difference: 5.30 (95% Crl: -0.49, 10.84), probability of superiority: 96.4% (table 1).

Conclusion:
In secondary analysis of an international randomized trial of critically ill participants with COVID-19, treatment with a P2Y12 inhibitor vs usual care was associated with improved quality of life at 90-days and may decrease symptoms of PASC following hospital discharge.
Abstract 14156: Promotion of Human Pluripotent Stem Cell-Engineered Cardiac Tissue Maturation by Non-Physiological Intermittent Hydrostatic Pressure
Authors: Wusiman Maihemuti , Murata Kozue , Iida Jun , Hakamada Keisuke , Sakaguchi Akane , Mosha Abulaiti , Saito Yuichi , Minatoya Kenji , Kimura Wataru , Masumoto Hidetoshi
Published: December 2023

Background:
The immaturity of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and hPSC-engineered cardiac tissues (ECTs) hinder their potential for cardiac regenerative therapy. Multiple studies have demonstrated the crucial role of ventricular loading pressure in cardiac repair and regeneration.

Hypothesis:
We postulated that hydrostatic pressure could enhance the maturation and functionality of the ECTs.

Methods:
To create ECTs, a mixture of hPSC-derived cardiovascular cells was co-cultured with Collagen I and Matrigel, then subjected to hydrostatic pressure. The functionality of the ECTs was assessed using a video-based system to measure contractile capacity, a flux analyzer to evaluate metabolic function, and a calcium indicator. Histological assessments were conducted to examine the structural maturation. CM maturation were evaluated through scRNA-seq. The trained ECTs were transplanted onto a rat myocardial infarction (MI) model followed by echocardiogram (N=3).

Results:
The optimized protocol consisting of intermittent pressure (1 hour/day) at 50 kPa (equivalent to 375 mmHg), for a duration of 3 days, preceded by a 2-week pre-culture period, remarkably enhanced the CM component and collagen alignment of the ECTs. This training led to increased expression of various genes associated with CM maturation. The trained ECTs exhibited a positive force-frequency relationship in terms of contractility, along with an elevation in peak calcium flux, indicating functional maturation. The training resulted in increased mitochondrial content and maximum respiration capacity, indicating metabolic maturation. Combination of the hydrostatic training and dynamic culture promoted vascular network formation of the ECTs. The maturation was dependent on the presence of endothelial cells (ECs), as ECTs without ECs failed to exhibit the maturation. The ECTs demonstrated a significant increase in ejection fraction of a rat MI model at 4 weeks post-transplantation (control vs training: 42.8±13.0 vs 80.7±8.5 %, P= 0.0045).

Conclusion:
The application of non-physiological and intermittent hydrostatic pressure training has led to significant maturation of ECTs, showcasing their therapeutic potential.