bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4137500: The Histone Methyltransferase MLL1 Regulates Notch Signaling and T Cell Phenotype During Pathologic Abdominal Aortic Aneurysm Development
Authors: Callow Brennan , He Xiaobing , Mangum Kevin , Bauer Tyler , Joshi Amrita , Obi Andrea , Gallagher Katherine A , Davis Frank
Published: November 2024

Objective:
Abdominal aortic aneurysms (AAA) are characterized by pathological vascular remodeling and an imbalance between anti-inflammatory regulatory T
H
cells (Tregs) and pro-inflammatory T
H
17 cells within the aortic wall. The mechanisms regulating CD4
+
T
H
cell differentiation during AAA development remain unknown. Recently, the histone methyltransferase, mixed lineage leukemia 1 (MLL1), has been shown to influence T
H
cell phenotype by directly altering key transcription factors for T
H
17 (RORγ) and Treg (FOXp3) differentiation in varying disease states. As such the objective of this study was to evaluate the role of MLL1 in promoting T
H
17 activity within AAA development and to determine key T
H
17 cell signaling pathways that are altered

Methods:
Single-cell sequencing was conducted on human AAAs and control tissue samples. For our murine model, C57BL/6 mice were injected with an AAV encoding a PCSK9 gain-of-function mutation and fed a saturated fat diet followed by either AngII infusion to induce AAAs (1 µg/kg/min) or saline. Mice with T-cell specific deletion of Notch1 signaling

(Notch1
f/f
CD4
cre+

) or MLL1 (

Mll1
f/f
CD4
cre+
)

were subjected to the AngII-induced AAA model and AAA diameters quantified. CD4+ T-cells were isolated by MACs and gene expression analyzed by qPCR as well as T-cell phenotype by flow cytometry. ChIP was used to evaluate histone 3 lysine trimethylation (H3K4me3).

Results:
Single-cell RNA sequencing of human aortic tissue revealed that the epigenetic enzyme MLL1 and Notch1 signaling were profoundly upregulated in human AAA CD4+ cells compared to non-aneurysmal control samples. Congruently, CD4
+
T
H
cells isolated from the murine AngII-induced AAA model displayed a predominance of T
H
17 phenotype and elevated expression of MLL1. Histone methylation was evaluated by ChIP in AngII-induced AAA CD4+ cells and demonstrated increased levels of the MLL1-mediated activation histone methylation mark, H3K4me3, on the Notch 1 promoter. Mice deficient in CD4
+
T
H
cell Notch signaling (

Notch1
f/f
CD4
cre+

) or MLL1 (

Mll1
f/f
CD4
cre+

) subjected to the AngII-induced murine model displayed significant reduction AAA development (n=10/group, p<0.05) with decreased CD4+ T
H
17 cell activity and reciprocal increase in Treg expression.

Conclusions:
MLL1, a histone methyltransferase, regulates Notch1 signaling and T-cell differentiation in AAA development, causing pathologic inflammation. This pathway may serve as a potential therapeutic target to prevent aortic dilation.
Abstract 4137543: Prevalence, Genetic Correlates and Prognostic Significance of an Apical Pseudo-Infarct Late Gadolinium Enhancement Pattern in
LMNA
-Mediated Cardiac Laminopathy
Authors: Castrichini Matteo , Garmany Ramin , Siontis Konstantinos , Ackerman Michael , Giudicessi John
Published: November 2024

Background:
Disease-causative variants in
LMNA
-encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular (AV) block, atrial fibrillation (AF) and ventricular arrhythmias (VA). Whether domain/variant-specific late gadolinium enhancement (LGE) patterns exist and carry prognostic significance is unclear.

Objective:
To determine if specific LGE patterns correlate with
LMNA
variant type/missense variant localization and clinical outcomes in a large cohort of cardiac laminopathy patients.

Methods:
Retrospectively, 621 genotype-positive arrhythmogenic/dilated cardiomyopathy patients were analyzed to identify those with a disease-causative variant in
LMNA
-encoded lamin A/C. After exclusion of patients without cardiac magnetic resonance data, pertinent demographic/clinical data was extracted from the electronic medical record. LGE distribution (subepicardial, midmyocardial, subendocardial, transmural) and location (septal, free wall, apical) patterns were analyzed by variant type (missense vs truncating) and missense variant localization (central rod domain vs tail domain) and correlated with advanced heart failure (AHF), MVA, AV block, AF and thromboembolic (TE) events.

Results:
70 out of 116 (60%)
LMNA
variant-positive (mean age 39±12, 43% male and 94% Caucasian) were included. Missense variants localizing to the C-terminal tail region showed a higher prevalence of transmural and apical LGE (Table). Amongst the 5 (7%) patients with this distinct apical pseudo-infarct LGE pattern, p.Arg471His-LMNA was identified in all cases. Among the 48/70 (69%) of patients with clinically manifest disease, p.Arg471His-LMNA-positive patients (n=6) were noted to have an increased prevalence of TE events [3 (50%) vs 5 (12%), 0=0.050] despite a reduced prevalence of AF [2 (33%) vs 32 (76%), p= 0.031]. No difference in AHF or MVA were observed, but AV block was less prevalent [1 (20%) vs 29 (74%), p= 0.029].

Conclusion:
p.Arg471His-LMNA causes a distinct apical pseudo-infarct LGE pattern associated with an increased risk of TE events and a decreased prevalence of AV block and AF. Future studies are needed to better refine the role of domain/variant-specific risk-stratification/anticoagulation in cardiac laminopathy.
Abstract 4137587: Need for Testing Standardization and Improved Treatment of Elevated Lipoprotein(a) at a Large Urban Academic Medical Center
Authors: Wong Willis , kao CINDY HSIN-YI , schneider Ruth , Navar Ann Marie , Rohatgi Anand , Khera Amit , Joshi Parag
Published: November 2024

Background:
Lipoprotein(a) [Lp(a)] is causally linked to ASCVD events and aortic stenosis. Some guidelines now recommend screening of Lp(a) at least once in an adult’s lifetime. Currently, there is inconsistency in measurement modality (mg/dL vs. nmol/L), but most guidelines recommending testing in nmol/L due to less variability and improved standardization. We sought to determine the Lp(a) measurement practices, including testing modality and downstream interventions, at a large academic medical institution.

Methods:
We evaluated all patient encounter data at UT Southwestern Medical Center (UTSW) between January 1, 2017 to December 31, 2021 for any Lp(a) measurement. High Lp(a) was defined as >50mg/dL or >125 nmol/L. Aggregate data were used to summarize patient demographics, relevant ASCVD co-morbidities, and lipid lowering prescriptions. Chart-review was conducted on patients with high Lp(a) to assess referrals to specialty clinics.

Results:
From 2017 to 2021, there were 1,065 Lp(a) measurements among 938 patients, representing fewer than 0.1% of all patients with labs at UTSW. Most were ordered by cardiologists (71%). Lp(a) tests ordered by cardiologists increased 69% annually but remained stagnant for other specialties (figure 1, lines). Median Lp(a) levels across all tests were 17mg/dL and 43nmol/L. Lp(a) was high in 30% of all initial tests. A higher proportion of tests ordered in 2021 by cardiologists (84%) were in nmol/L, the recommended standard, compared with other specialties (55%) (figure 1, bars). Patients with high Lp(a) found by a non-cardiologist were infrequently referred to cardiology (16%), and 53% of patients with high Lp(a) were prescribed lipid lowering therapy within 3 months.

Conclusion:
Lp(a) testing at a major academic medical center was rare and only marginally increased during the 5-year study period. Measurement frequency and assay varied widely between specialties, and there were potential opportunities for downstream interventions. In addition to improving awareness of Lp(a), there is an opportunity to standardize practice patterns regarding its measurement and implications.
Abstract 4137594: Intrinsic Capacity Trajectories and Cardiovascular Disease Among Chinese Older Adults: A Population-Based Longitudinal Study
Authors: GUO ZHITING , Chen Yuling , Dennison Himmelfarb Cheryl , Koirala Binu , Li Jiaying , jin jingfen
Published: November 2024

Background:
WHO defined intrinsic capacity (IC), a composite of physical and mental capacities, is a marker of healthy aging. Monitoring IC trajectories in older adults may guide preventative strategies and delay negative health outcomes. With the rapidly increasing proportion of older adults and the high prevalence of cardiovascular disease (CVD) in China, this study aimed to identify IC trajectories over time and determine whether IC trajectories can predict CVD outcomes.

Hypothesis:
The IC trajectory among Chinese older adults is heterogeneous; the decline of IC will be associated with increased CVD.

Methods:
The study used data from five waves (2011 to 2020) of the China Health and Retirement Longitudinal Study (CHARLS). A total of 3,336 adults aged 60 years or older without CVD during the baseline survey in 2011 (T1), who completed the follow-ups in 2013 (T2) and 2015 (T3) were included to determine IC trajectory. IC was assessed through five domains (locomotion, sensory, vitality, cognition, and psychology) using the WHO framework. The CVD outcomes were determined by self-reported diagnoses of heart disease or stroke in the 2020 (T5) wave. A group-based trajectory model (GBTM) was used to identify IC trajectory, and logistic regression was employed to explore the association between IC trajectory groups and CVD outcomes adjusting for covariates.

Results:
Three IC trajectory groups were identified (Fig 1): high IC-stable group (13.40%), medium IC-stable group (56.12%), and low IC-decline group (30.48%). By the 2020 follow-up, 1204 participants (36.1%) reported CVD diagnosis. Adjusted for sociodemographic, lifestyle factors (smoking, drinking), and cardiovascular metabolic factors (hypertension, diabetes, dyslipidemia), compared to the high IC-stable group, the low IC-decline group had 63.7% higher odds of CVD (OR=1.637, 95%CI=1.268-2.114), and medium IC-stable group had 7.1% higher odds of CVD (OR=1.071, 95%CI=0.851-1.349).

Conclusion:
IC trajectory among Chinese older adults is heterogeneous, and IC declines predict higher odds of CVD onset. Regular monitoring of IC and tailored intervention to improve IC may facilitate CVD prevention.
Abstract 4137620: Serum Acylcarnitines Predict Longitudinal Deteriorations in Cardiac Function and Adverse Outcomes in Older Adults
Authors: WONG JIE JUN , Gao Fei , Tan Glades , Loh Johnathan , Teo Loon Yee , Ewe See Hooi , Wee Hai Ning , Chua Kee Voon , Ching Jianhong , Tan Ru , Kovalik Jean Paul , Koh Angela
Published: November 2024

Background:
Circulating acylcarnitines (ACs), biomarkers of mitochondrial β-oxidative function, are linked to cardiovascular diseases (CVD) yet the extent to which ACs relate to prospective cardiac aging remains uncertain. We investigate the longitudinal associations between ACs, cardiac function, and clinical outcomes.

Methods:
A population-based sample of community older adults without CVD underwent baseline serum metabolomic profiling and interval echocardiography at five years. Incident hospitalizations were prospectively tracked from 2014 to 2021. Multiple linear regression adjusted for significant clinical variables.

Results:
Of 202 participants (baseline 65±11.9 years, 49.3% women), we observed interval increases in risk factors (hypertension 39% vs 52.2% p<0.001; dyslipidemia 39% vs 50% p=0.034; diabetes 11.7% vs 18.8% p=0.035; smoking 13.2% vs 24.7% p=0.003; waist circumference 81±10.1 vs 86±9.9cm p<0.001) during follow-up (4.9±0.4 years). These changes paralleled E/e’ increases (8.9±2.6 vs 11.1±3.3 p<0.001) and E/A decreases (1.09±0.4 vs 1.0±0.4 p<0.001). Baseline C8:1 (β=0.182 p=0.011), C22:3 (β=0.148 p=0.047), C22:5 (β=0.210 p=0.003), C5:1 (β=-0.142 p=0.048), and C16-OH (β=-0.156 p=0.028) levels were associated with E/e’ change over time while C6 (β=0.163 adj. p=0.019), C8:1 (β=0.137 adj. p=0.047), C10:2 (β=0.153 adj. p=0.035), C14:3 (β=0.147 adj. p=0.031), and C16:1-OH/C14:1-DC (β=0.158 adj. p=0.022) were associated with E/A change. At follow-up, baseline C8:1 (β=0.178 adj. p=0.006) and C10:3 (β=0.145 adj. p=0.024) were associated with E/e’ while C4-DC/C6-OH (β=-0.004 adj. p=0.034) was associated with E/A. Baseline C22:2 predicted incident hospitalizations (HR=1.20 95%CI 1.03-1.39, adj. p=0.018).

Conclusion:
Circulating ACs independently predicted declining cardiac function and adverse outcomes over five years among older adults without CVD. The prognostic effect of ACs should be translated to strategies targeting mitochondrial health in cardiac aging prevention.
Abstract 4137636: Cardiac radiation dose and changes in physical activity and quality of life in patients with locally advanced lung cancer
Authors: Ko Kyunga , Yegya-Raman Nikhil , Han Ivy , Mitchell Joshua , Zou Wei , Levin William , Barrett Leanne , Bravo Paco , DI CARLI MARCELO , Cohen Roger , Hutton Sandra , Jabbour Salma , Jung Wonyoung , Keltz Jonathan , Mak Raymond , Nagda Suneel , Ohri Nitin , Robinson Clifford , Smith Amanda , Sun Lova , Soike Michael , Walls Gerard , Wang Jessica , Feigenberg Steve , Ky Bonnie
Published: November 2024

Background:
Physical activity is associated with prognosis in cancer. However, in non-small cell lung cancer (NSCLC), a high cardiovascular (CV) population, the relationships between RT dose, physical activity, and CV patient-reported outcomes remain unclear. We determined the associations between cardiac radiation dose-volume metrics and changes in physical activity and quality-of-life (QoL) in patients treated with definitive chemoradiation.

Methods:
NSCLC participants treated with chemoradiation were enrolled in a multi-center longitudinal cohort study. Self-reported physical activity via Godin–Shephard Leisure-Time Physical Activity Questionnaire (Godin) and QoL via Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue and Dyspnea Scales were collected at baseline, end of RT, 6, and 12 months post-RT. Changes in Godin and FACIT scores over time were examined using linear mixed-effects models. Multivariable linear regression via generalized estimating equations assessed the associations between: 1) mean heart dose (MHD) and longitudinal changes in physical activity and QoL, and 2) concurrent changes in physical activity and FACIT scores.

Results:
Across 101 participants, the mean age was 66 years, with 57% male, 66% White, and 25% Black. The median (Q1, Q3) MHD was 10.8 Gy (6.1,16.3). Very low physical activity [9 (0, 25)], high dyspnea [4 (1, 9)], and low fatigue [39 (31,46)] were reported at baseline. With chemoRT, there was a significant worsening of physical activity (
P
= 0.03), fatigue (
P
< 0.001), and dyspnea (
P
< 0.001). Each 1-Gy increase in MHD was associated with a modest decline in physical activity (-0.28; 95% CI -0.53, -0.02,
P
= 0.03), and higher physical activity was associated with a concurrent decrease in fatigue (
P
< 0.001) and dyspnea (
P
= 0.007) (Table).

Conclusions:
In locally advanced NSCLC, physical activity levels prior to RT were very low, and higher cardiac radiation dose was associated with a further decline in physical activity. Increased physical activity was associated with concurrent decreases in fatigue and dyspnea. Strategies to promote physical activity may result in improved QoL in this high CV group.
Abstract 4137672: Prevalence, Clinical Characteristics, and Outcomes in Heart Failure with Improved Ejection Fraction by Sex
Authors: Liang Yilin , Lee Keane , Parikh Rishi , Ambrosy Andrew , Tan Thida , Hamilton Steven , Pabon Porras Maria , Vardeny Orly , Naderi Sahar , Ku Ivy , Vasti Elena , Sandhu Alexander , Go Alan , Adatya Sirtaz , Bhatt Ankeet
Published: November 2024

Background:
Heart failure with improved ejection fraction (HFimpEF) is a growing clinical entity. While males are more likely to present with HFrEF, there remains little understanding of how sex relates to the epidemiology, predictors, and progression of HFimpEF.

Research Question:
What are the differences in epidemiology, clinical characteristics, medical management, and outcomes in patients (pts) with HFimpEF based on sex.

Methods:
We identified adults age ≥18 years with incident HFrEF (EF ≤40%) between January 2013 and December 2018 within Kaiser Permanente Northern California, an integrated health system serving >4.5 million members. HFimpEF was defined as subsequent EF measurement >40% within the following 12 months. Sex was based on self-report. Among pts with HFimpEF, we examined guideline-directed medical therapy (GDMT) use at time of incident HFimpEF, and at 6- and 12-months post-HFimpEF, stratified by sex. The incidence of worsening HF (WHF) events and all-cause death was assessed in a landmark analysis at 12 months post-HFrEF. We compared event rates between patients with HFimpEF and persistent HFrEF using Cox proportional hazards models adjusted for baseline age and EF.

Results:
Among 12,639 patients with incident HFrEF (female: 36%), 33% experienced HFimpEF. Females were more likely to experience HFimpEF in the 12 months following HFrEF than males (34% vs. 32%, p<0.01). Among pts with HFimpEF, treatment with GDMT was similar among males and females and declined after incident HFimpEF in both sexes (Figure, Panel A). Females had similar rates of WHF or all-cause death compared to males (adjusted [a]HR: 1.10, 95% CI: 0.96, 1.26, P=0.17). Compared with those with persistent HFrEF, pts with HFimpEF had lower rates of WHF or all-cause death, a finding which was consistent by sex (male: aHR: 0.55, 95% CI: 0.50 to 0.61, female: aHR: 0.54, 95% CI: 0.48 to 0.62; Pinteraction by sex=0.78; Figure, Panel B).

Conclusions:
HFimpEF is more common among females compared to males, but prognosis is similar. Despite similar medical therapy, GDMT discontinuation after EF improvement is prevalent. Improvement in EF is similarly associated with improved outcomes across sex. Further data are needed to elucidate the differential etiologies of HF by sex.
Abstract 4137718: Coronary Artery Calcium for Risk Stratification of Heart Failure Mortality
Authors: Mhaimeed Omar , Dardari Zeina , Khorsandi Michael , Dzaye Omar , Sharma Kavita , Nasir Khurram , Berman Daniel , Budoff Matthew , Shaw Leslee , Rumberger John , Miedema Michael , Blaha Michael
Published: November 2024

Background:
There is increasing interest in predicting heart failure (HF), a major cause of morbidity and mortality that exerts a significant financial burden. The role of coronary artery calcium (CAC), an accessible and inexpensive test, in predicting long-term HF mortality amongst asymptomatic adults remains unknown.

Objectives:
To determine if CAC burden is associated with HF-related mortality in the primary prevention population.

Methods:
The study included 66,636 primary prevention patients from the Coronary Artery Calcium Consortium. Multivariable competing risks regression was used to assess the association between CAC and HF-related mortality adjusting for demographics and traditional risk factors.

Results:
The mean age was 54.4 years, 67% male, 89% white, and 55% had CAC >0. A total of 260 HF-related mortality events were observed during a median follow up of 12.5 years, 75.3% of which occurred among those with a baseline CAC score >100. Compared with a CAC = 0, there was a stepwise higher risk (P < 0.005) of HF mortality for CAC 1-100 (subdistribution hazard ratio [SHR]: 2.27; 95% CI: 1.3-3.99), 100-400 (SHR: 3.68; 95% CI 2.1-6.43), and >400 (SHR: 7.05; 95% CI 4.05-12.29). This increasing risk of HF mortality across higher CAC scores persisted across age groups, sex, and in the intermediate and high-risk groups as calculated by the pooled cohort equation (PCE) and the PREVENT equation.

Conclusions:
Higher CAC is associated with increasing incidence of long-term HF-related mortality in the primary prevention population, particularly intermediate and high-risk patients. Early preventive approaches in patients with high CAC must focus on preventing heart failure and ASCVD with lifestyle changes and medications.
Abstract 4137735: Chronic Oxidative Stress Induces Hypertension and Abdominal Aortic Aneurysm in Chemogenetic Mice Model
Authors: Das Apabrita , Waldeck-Weiermair Markus , Yadav Shambhu , Covington Taylor , Spyropoulos Fotios , Pandey Arvind , Michel Thomas
Published: November 2024

Background:
Aortic aneurysms account for ~10,000 deaths annually in the USA. Oxidative stress is implicated in both abdominal (AAA) and thoracic (TAA) aneurysm formation, but the mechanisms are incompletely understood. We used a chemogenetic approach to modulate oxidative stress in the vascular wall by creating a transgenic mouse (DAAO-TG
Tie2
) that expresses yeast D-amino acid oxidase (DAAO) driven by the endothelial Tie2 promoter. DAAO generates the reactive oxygen species hydrogen peroxide from D-amino acids. Vascular tissues contain L-amino acids, so yeast DAAO is quiescent until DAAO-TG
Tie2
mice are provided with D-amino acids. Here we characterize the cellular and molecular consequences of vascular oxidative stress in DAAO-TG
Tie2
mice.

Hypothesis:
Chronic oxidative stress in the vascular wall causes arterial dysfunction.

Aim:
To characterize the phenotype of DAAO-TG
Tie2
mice after oxidative stress induction in vascular endothelium.

To identify the mechanisms whereby vascular oxidative stress causes arterial dysfunction and hypertension.

Methods:
Systolic blood pressure and aortic sonography were measured weekly in D-alanine-fed DAAO-TG
Tie2
. Proteomic analyses were used to identify mechanistic targets, which were validated using biochemical and immunohistochemical methods.

Results:
D-alanine-fed DAAO-TG
Tie2
mice develop systolic hypertension and abdominal but not thoracic aortic aneurysms; treated mice die in >3 months with burst abdominal aortic aneurysms. Transgene expression is similar in abdominal and thoracic endothelium. Levels of oxidative stress markers (oxidized proteins, lipid, and DNA) were similar in thoracic and abdominal aorta. Proteomic analyses established phenotypic switching in abdominal but not thoracic aorta, and also revealed activation of the oxidant-activated kinase ASK1 and of the MAP kinase cascade in abdominal but not thoracic aorta. Immunoblot analyses showed a marked decrease in JNK1 phosphorylation by phosphatase DUSP3 and an increase in vascular KLF4, leading to phenotypic switching of contractile to synthetic VSMCs.

Conclusion:
Chronic chemogenetic oxidative stress induces hypertension and abdominal aortic aneurysm formation caused by KLF4-dependent VSMC phenotypic switching.
Abstract 4137737: Demographics and Factors Influencing Mortality Among Cardiac Angiosarcoma Patients: An Analysis of the SEER Database
Authors: Khan Rozi , Goyal Aman , Wali Agha , Yasinzai Abdul Qahar Khan , Tareen Bisma , Khan Marjan , Ullah Hafeez , Iqbal Asif , Ghafouri Sayed Ab Reshad , Mahmood Ahmed , Sohail Amir , Pooja Sethi , AlJaroudi Wael , Ullah Asad
Published: November 2024

Background and Aims:
Cardiac angiosarcoma is a rare and highly aggressive cancer originating from the endothelial cells lining the heart. It accounts for approximately 30% of all primary cardiac tumors. Given its aggressive nature and poor prognosis, it is critical to enhance our understanding of its epidemiology and the factors influencing mortality.

Methods:
The Surveillance, Epidemiology, and End Results (SEER) database was utilized to gather data spanning from 2000 to 2021 using the International Classification of Diseases for Oncology (ICD-O-3), anatomical codes (C38.0-Heart), and histological code 9120.

Results:
We identified 194 patients with cardiac angiosarcoma, of which 102 were males and 92 were females. The majority of patients were aged 50 years or younger (59%). Non-Hispanic whites constituted the largest group (56%), followed by non-Hispanic blacks (18%), and Hispanics (16%). Mortality data showed that 91% of the diagnosed patients died (n=176), with a mean survival period of 15 months after diagnosis. The overall survival rate at 1 year was 0.461 (95% CI: 0.39-0.53), at 3 years was 0.09 (95% CI: 0.05-0.14) and at 5 years was 0.052 (95% CI: 0.03-0.10). Advanced age (51-70 years) compared to the 0-50 year age group (HR: 0.57; 95% CI: 0.003-1.14; p=0.049), distant stage (HR: 0.91; 95% CI: 0.01-1.83; p=0.047), patients who did not receive therapeutic radiation therapy compared to those who did (HR: 2.69; 95% CI: 0.10-5.28; p=0.042), and patients who did not undergo surgical resection for angiosarcoma compared to those who did (HR=1.232; 95% CI: 0.69-1,77; p<0.001) were factors associated with increased mortality. Female gender (p=0.248, as compared to males), different races of non-Hispanic White (p=0.849), non-Hispanic Black (p=0.34), non-Hispanic Asian or Pacific Islander (p=0.24), as compared to Hispanics, tumor sizes of 6-10 cms (p=0.957), or more than 10 cm (p=0.273), as compared to < 5 cm, grade of tumor (III; p=0.682, and grade IV; p=0.281, as compared to grade I), median household income of more than 65000 USD (p=0.069) as compared to less than that, and no chemotherapy (p=0.851) compared to those that received chemotherapy, were not associated with a significant increase in mortality.

Conclusions:
Cardiac angiosarcoma is associated with a high mortality rate. Factors contributing to increased mortality include advanced age, distant stage of disease at diagnosis, not receiving radiation therapy, and not undergoing surgical resection.
Abstract 4137768: Evaluation of Therapeutic Intensification for Uncontrolled Hypertension Using Different Sources of Electronic Health Records
Authors: Ni Liang , Juan Rachelle , Harrison Teresa , An Jaejin
Published: November 2024

Background:
Healthcare system level interventions to monitor therapeutic intensification for uncontrolled blood pressure (BP) may address potential therapeutic inertia, however, the best methods to evaluate therapeutic intensification using different sources of electronic health records are unknown.

Question:
To what extent do medication orders and pharmacy data provide comparable or distinct evaluations of therapeutic intensification?

Methods:
We identified adults with uncontrolled hypertension (systolic BP ≥140 or diastolic BP ≥90 mm Hg) in an outpatient encounter (index) from Kaiser Permanente Southern California in 2018. We included patients with new antihypertensive medication orders at the index encounter. We calculated therapeutic intensification score (TIS), a proportional measure of prescribed daily dose to maximum recommended daily dose of antihypertensive medications using two data sources: (1) medication orders including dose, directions for use, discontinuation order; (2) pharmacy fill data including strength, days’ supply, and quantity within 14 days after the index. Therapeutic intensification was determined by comparing the new dose at index and the previous dose [delta TIS (new dose – previous dose) >0]. Differences in TIS and the percentage of concordance using two methods were compared using descriptive statistics.

Results:
We included 75,935 patients with medication orders at the index encounter. Using medication order data, 84% increased the dose of antihypertensive medications with a median TIS (25
th
, 75
th
) of 0.25 (0.13, 0.50). Among the total, 80% (n=61,485) filled their prescriptions. Among those who filled their prescriptions, 84% and 85% increased the dose using medication order and pharmacy data, respectively, with 95% concordance between the two methods. Mean (SD) differences in dose change was -0.06 (0.55) between the two methods (
p
<0.001).

Conclusion:
A large portion of patients with uncontrolled BP failed to fill their new prescriptions, underscoring the value of utilizing medication order data to evaluate therapeutic intensification. For those who filled prescriptions, only minimal differences were observed between the evaluations using medication orders and pharmacy data.
Abstract 4137804: Associations between falls and other serious adverse events and antihypertensive medication in individuals with dementia: An observational cohort study
Authors: Fujiwara Takeshi , Koshiaris Constantinos , Cai Ting , Wang Ariel , Lee Joseph , Lay-Flurrie Sarah , Banerjee Amitava , Clegg Andrew , Payne Rupert , Swain Subhashisa , Ogden Margaret , Hoshide Satoshi , Kario Kazuomi , Hobbs Richard , McManus Richard , Sheppard James
Published: November 2024

Background:
The balance of benefits and risks associated with lowering blood pressure levels in individuals with dementia remains controversial with a lack of evidence for possible harms associated with antihypertensive treatment (AHT).

Objectives:
We examined the association between AHT and serious adverse events (SAEs) in individuals with dementia compared to those without.

Methods:
This was a retrospective analysis using nationally representative, UK general practice population between 1998 and 2018, using data from electronic health records (Clinical Practice Research Datalink, GOLD). Individuals included were age ≥40 years and not previously prescribed AHT. Diagnosis of dementia was based on standardised clinical codes. The primary outcome was the first hospitalisation or death from a fall within 10 years of the follow-up period. Secondary outcomes were first hospitalisation or death from hypotension, syncope, and fracture. Cox regression analyses, adjusted for propensity score were used to assess the risk of SAEs.

Results:
In a population of 1,219,732 individuals, 23,510 had dementia. Antihypertensive medications were newly prescribed in 4,062/23,510 (17.3%) individuals with dementia and 142,385/1,196,222 (11.9%) individuals without dementia in the 12 months exposure period. In individuals with dementia, AHTs were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.15, 95% confidence interval [CI] 1.08, 1.22), hypotension (aHR 1.51, 95%CI 1.29, 1.78), syncope (aHR 1.34, 95%CI 1.11, 1.61), but not fracture (aHR 1.05, 95%CI 0.96, 1.15). In individuals without dementia, the association between AHT and SAEs was similar, with an increased risk of hospitalisation or death from falls (aHR 1.07, 95%CI 1.05, 1.10). However, absolute risk of falls with AHT per 10,000 individuals per year was significantly higher in individuals with dementia (47, 95%CI 26, 70) compared to those without (14, 95%CI 10, 18). The absolute risks of hypotension and syncope with AHT were also higher in the individuals with dementia compared to those without.

Conclusions:
AHT was associated with increased risk of SAEs in individuals with and without dementia, however, the absolute risk of harm from falls was more than double in individuals with dementia. Clinicians, patients, and their carers should consider these risks before starting new antihypertensive medications, particularly in the context of dementia, although they remain small.
Abstract 4137810: Association of Sociodemographic Characteristics on Costs of Care in Patients with Obstructive Hypertrophic Cardiomyopathy
Authors: Reza Nosheen , Butzner Michael , Batra Kirti , Amos Qiana , Buikema Ami , Anderson Amy , Shreay Sanatan , Owens Anjali
Published: November 2024

Introduction:
No evidence exists on the impact of sociodemographic characteristics on costs of care for obstructive hypertrophic cardiomyopathy (oHCM). Therefore, we evaluated 5-year cumulative costs by age, sex, and race/ethnicity.

Methods:
Retrospective cohort study of adults diagnosed with oHCM (January 2013 to December 2021) using Optum claims and electronic medical record data. Patients with ≥2 claims for HCM (ICD-9 and-10) at least 30 days apart (index date = earliest oHCM claim) with ≥1 additional oHCM claim or septal reduction therapy, 6-months pre-index and 5-year post-index continuous enrollment were included. HCM-related cumulative costs (2022 CPI adjusted) were reported for medical (ambulatory [AB]: office [OV] visits, outpatient [OP] visits); emergency room [ER] visits; inpatient admissions (IP); and pharmacy (Rx).

Results:
Among 5,129 patients with oHCM, 52% were female (mean age 63.9 ± 14.3 years; 77.6% non-Hispanic White; 40% Medicare). Compared to females (Table), male patients had greater costs including total ($71,581 vs $63,710, p= 0.014), medical ($70,395 vs $62,455, p= 0.013), ambulatory ($16,024 vs $10,776, p<0.001), OV ($1,906 vs $1,573, p<0.001), and OP ($14,118 vs $9,202, p<0.001). Compared with White patients, Black patients had significantly greater IP costs ($54,572 vs $42,686, p= 0.01), Hispanic patients had greater ER costs ($1,724 vs $791, p<0.001), and Asian patients had greater OV costs ($2,094 vs $1,800, p<0.001). Patients aged 18-39 years had greater costs across all categories (p<0.001; IP=NS), except Rx. Patients aged 40-54 years had the highest Rx costs ($1,557, p<0.001), followed by 18-39, 55-64, 65-74, 75+ years ($1,528; $1,329; $1,197; $867), respectively.

Conclusions:
For oHCM patients
,
being male and age 18-39 years was associated with increased HCM-related healthcare costs. Differences in cost across race/ethnicity exist, including greater IP and ER costs for Black and Hispanic patients, respectively. Future research is required to understand the source of these differences among oHCM patients.
Abstract 4137833: The plasma cell-free transcriptome non-invasively profiles the immune response and myocardial damage in immune checkpoint inhibitor-induced myocarditis.
Authors: Raissadati Alireza , Zhou Xuanyu , Chou Harrison , Huang Yuhsin , Hernandez Arturo , Loa Sharon , Xu Anne , Sun Yin , Zhu Han , Wu Sean
Published: November 2024

Introduction:
Immune checkpoint inhibitor-induced myocarditis (ICI-m) is a severe complication of cancer immunotherapy, marked by cardiac inflammation. Despite its high mortality rate, diagnosing ICI-m remains challenging due to the lack of sensitive and non-invasive diagnostic modalities. Plasma cell-free mRNA (cf-mRNA) has recently been highlighted as a promising tool for non-invasive tissue profiling.

Hypothesis:
The plasma cf-mRNA profile contains disease-specific immune and tissue transcriptomic signatures of ICI-m that can be leveraged for disease-specific precision diagnostics.

Aims:
To establish and validate a novel cf-mRNA bench and bioinformatic pipeline for noninvasive profiling of the immune and tissue landscape of patients with ICI-m.

Methods:
We isolated, DNase-treated, and sequenced bulk cfRNA from frozen plasma of patients with ICI-treated cancer patients with no autoimmunity (group A, n=5), extracardiac autoimmunity (group B, n=7), and ICI-m with or without extracardiac autoimmunity (group C, n=10). Publicly available healthy control cfRNA was downloaded (n=30) as external controls. We used cell type-specific gene panels curated from single-cell RNA-sequencing datasets of circulating immune cells and cardiac cells for cellular deconvolution of the cf-mRNA. Signature scores of the sum of the counts of each cell type-specific gene were used to compare cell type contributions between patient groups.

Results:
Cancer and inflammatory gene pathways were significantly enriched in the cf-mRNA of all ICI-treated cancer patients. Cardiac pathways and conduction genes were significantly enriched in group C vs. A and B patients. Signature scores of Temra CD8+ T cells and cardiomyocytes, and gene expression of CCL5 and MYH6 were elevated in group C patients. Our custom ICI-m classifier containing 3 cardiac- and 3 immune cell-specific genes differentiated group C from A (AUC 0.903, 95% CI 0.858-0.903) and B patients (AUC 0.983, 95% CI 0.970-0.983) effectively, outperforming a diagnostic classifier obtained from unsupervised feature selection from all differentially expressed genes.

Conclusions:
Using our novel plasma cf-mRNA platform, we developed a diagnostic classifier that captures the disease-specific immune and tissue transcriptomic signatures of ICI-m, highlighting the advantages of this disease-specific approach over conventional biomarker discovery, and demonstrating the broader implications of the platform for the field of precision diagnostics.
Abstract 4137845: A single-cell lung atlas of human pulmonary arterial hypertension
Authors: Dai Zhiyu , Yi Dan , Zhao Hanqiu , Hong Jason , Fallon Michael
Published: November 2024

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

Hypothesis:
We hypothesis that single-cell RNA sequencing analysis can help understand the cellular and molecular mechanisms that drive the disease initiation and progression.

Methods:
10 healthy donors, 10 idiopathic PAH, 10 drug and toxin induced PAH, 10 systemic and pulmonary shunting induced PAH patients from both male and female, and different ethical groups and races, and ages were obtained from PHBI. Lung tissue specimens were processed for fixed scRNA-seq. The cell proportion change, gene expression, and pathway analysis were evaluated between different disease subclasses, sex, age on different cell types.

Results:
Our analysis reveals 317,414 cells, 33 clusters and 9 major cell types, including endothelial cells (ECs), alveolar cells, fibroblast, smooth muscle cells (SMCs), pericytes, myeloid cells, lymphocytes, airway epithelial cells, platelet. Cell proportion analysis demonstrated an increase in the proportions of venous ECs, adventitial fibroblasts and myofibroblasts, alveolar macrophages, B cells, plasma cells and a reduction in capillary ECs 2 and pericytes in PAH lungs. KEGG Pathway analysis showed that upregulated pathways related Herpes simplex virus 1 infection, ECM-receptor interaction, Complement and coagulation cascades, Hedgehog signaling, TGF-beta signaling pathway, and downregulated pathways related to IL-17 signaling, TNF signaling, MAPK signaling pathway were enriched in the PAH patients. Female PAH patients exhibit an increase of myofibroblasts and platelets proportion compared to male PAH patients. MsigDB Hallmark Pathway analysis showed that p53 pathway was upregulated, whereas Inflammatory Response, Hypoxia, Epithelial Mesenchymal Transition were downregulated in female PAH patients. PAH patients older than 21 years exhibit an increase in the cell proportion of Platelet, SMCs, Arterial ECs and Venous ECs, and alveolar macrophages and a reduction of B cells and plasma cells.

Conclusions:
Our integrated analysis of human PAH lung atlas dataset provides a comprehensive understanding of lung cell populations and molecular signature in PAH patients with different sex, age and subclasses
Abstract 4137854: Effect of Sacubitril/valsartan on Left Ventricular Tissue Characterization in Heart Failure with Left Ventricular Ejection Fraction Below 50%
Authors: Fujimoto Naoki , Mizutani Hana , Nakamori Shiro , Kokawa Takanori , Sato Yuichi , Goto Itaru , Ishida Masaki , Tanigawa Takashi , Sakuma Hajime , Dohi Kaoru
Published: November 2024

Background:
The effects of sacubitril/valsartan (ARNI) on myocardial tissue characterization in heart failure (HF) with left ventricular ejection fraction (LVEF) <50% are still unclear.

Objective:
The present study investigated the effects of 9 months of ARNI treatment on LV structure and myocardial tissue characteristics in HF with LVEF <50% using cardiac magnetic resonance (CMR).

Methods:
This study was a prospective, 2-arm, randomized, open-label clinical trial (SAVE-HF). Sixty-four HF outpatients with LVEF<50% were randomized 1:1 from ACE inhibitor/ARB to ARNI (ARNI group) or control group (continued ACE inhibitor/ARB). CMR was performed to evaluate LV structure and tissue characteristics, including changes in LV extracellular volume fraction (delta ECV) before and after the 9-month period. The primary endpoint was difference in ECV between the two groups. Secondary endpoints included changes in LV volumes and mass, LVEF, extracellular mass (ECM) calculated as LV mass times ECV/100, and intracellular mass (ICM) calculated as LV mass minus ECM.

Results:
A total of 59 of 64 stable patients (68±12 years; 52 men) completed the 9-month intervention followed by repeated CMR. ARNI decreased systolic BP levels from the first month by approximately 10 mmHg. ARNI group exhibited significant reductions in LV end-diastolic and end-systolic volumes and LV mass. While LVEF and ECV remained unchanged (31.6±5.0 vs. 31.9±5.0%, p=0.26), both ECM and ICM significantly decreased after ARNI. In the control group, systolic BP, LV volumes and LV mass, ECV, ECM and ICM were unchanged. Comparing the two groups, while delta ECV was not significantly different, delta ECM was greater in ARNI group than control group (-3.6±7.3 vs. 0.2±5.3 g, p=0.025), indicating improved LV tissue characteristics.

Conclusions:
ARNI reduced LV volume and LV mass, accompanied with reduction of both ECM and ICM, and consequently unchanged ECV. These findings may suggest that ARNI may improve LV tissue characteristics and protect from LV remodeling in HF patients with their LVEF<50%.
Abstract 4137928: Race-Dependent Association of Inflammation and Cholesterol with Cardiovascular Mortality in US Population
Authors: Li Pengfei , Zhang Yiwen , Ji Hongwei
Published: November 2024

Background:
Inflammation and cholesterol jointly contribute to cardiovascular disease and mortality. The relative contributions of inflammation and cholesterol to the risk of future cardiovascular events might shift according to pre-existing traits of each individual. Whether the association of inflammation and cholesterol with cardiovascular mortality differ by race remains unclear.

Method:
We sampled 12,726 participants from NHAENS III who were categorized as non-Hispanic White, non-Hispanic Black or Mexican Americans. In all race groups, we used the Cox proportional hazard regression model to relate log-transformed CRP and LDL-C levels to CVD deaths. All models simultaneously included CRP and LDL-C, and were adjusted for age, current smoking, hypertension, diabetes mellitus, body mass index, lipid-lowering medications, total cholesterol and family income.

Results:
12,726 participants (53.4% female, mean age 46.8 ± 19.7 years) including 5648 non-Hispanic White (44.4%), 3484 non-Hispanic Black (27.4%) and 3594 Mexican-American (28.2%) were followed up for a median 26.3 years , and 1905 cardiovascular deaths were documented. After adjusting for cardiometabolic risk factors, per 1 SD increase in log-transformed CRP was associated with 14% (HR 1.14 [95% CI, 1.08-1.21], P < 0.001) and 13% (HR 1.13 [95% CI, 1.04-1.23], P = 0.001) higher risk of CVD mortality in non-Hispanic White and non-Hispanic Black respectively, while the association was neutral in Mexican American. Notably, per 1 SD increase in LDL-C was not associated with CVD mortality in all race groups (P > 0.05 for all).

Conclusion:
After a follow up of median 26.3 years, we found that, in non-Hispanic White and Black individuals, but not in Mexican American, inflammatory was a stronger predictor of cardiovascular mortality, compared to cholesterol.
Abstract 4137975: 9-Year Longitudinal Assessment of the 12-lead Electrocardiogram of Volunteer Firefighters
Authors: Bae Alexander , Dzikowicz Dillon , Lai Chi-Ju , Brunner Wendy , Krupa Nicole , Carey Mary , Tam Wai Cheong , Yu Yichen
Published: November 2024

Introduction:
In the US, the most common cause of death among active-duty firefighters is sudden cardiac death (SCD). Underlying heart diseases are important propagator of ventricular tachyarrhythmias that cause SCD. The objective of this abstract is to assess the incidence of underlying heart disease, identified on 12-lead electrocardiograph (ECG), that may place firefighters at greater risk of SCD.

Methods:
We digitalized 12-lead ECGs recorded among firefighters who visited a firefighter health screening program at least 4 times from 2011-2019. We extracted the interval measurements (Heart Rate, T-axis, QRS-axis, QRS duration, QTc duration) and interpretation statements from each of the 12-lead ECGs and grouped potential propagators of ventricular tachyarrhythmias including left ventricular hypertrophy (LVH), coronary artery disease (CAD), and cardiac conduction disease. We used simple mean imputation to handle missing data. Descriptive statistics including means and frequencies were used to analyze the sample.

Results:
Among 465 firefighters (90.1% male) with a mean age of 47.1 (±13.6) whom 1,296 12-lead ECGs were analyzed, 21.5% (n=278) of Heart Rate, 0.39% (n=5) T-axis, 26.4% (n=342) QRS-axis, 40.0% (n=518) QRS duration, 5.40% (n=70) QTc duration were abnormal. In addition to intervals, the 12-lead ECGs generated 1,970 interpretation statements of which 28.2% (n=555) were deemed possible pathoanatomical substrates including 3.1% (n=34) LVH, 24.7% (n=137) CAD, and 69.2% (n=384) cardiac conduction diseases. Among cardiac conduction diseases, intraventricular conduction disease was the most prevalent (n=204, 36.8%), followed by vertical axis (n=70, 12.6%), right bundle branch block (n=59, 10.6%), left anterior fascicular block (n=34, 6.1%), and left bundle branch block (n=17, 3.1%). Interestingly, we did not observe a temporal relationship regarding the number of pathoanatomical substrates over the screening period.

Conclusions:
Nearly 30% of the interpretation statements generated from 12-lead ECGs were indicative of possible pathoanatomical substrates that cause SCD, which reflects the apparently negative effect of fire suppression activity on one’s cardiopulmonary health. Our result justifies the imperative need of effective prevention method for cardiac conduction diseases among firefighters. Further research is needed to collect 12-lead ECG systematically amongst other measures such as diet and BMI which reflect work culture and lifestyle of firefighters.
Abstract 4137996: Effects of Empagliflozin on diuresis in heart failure: Results from the CINNAMON-study and in-vivo experiments
Authors: Sinha Frederick , Klatt Susanne , Rietmann Alexander , Schoepperl Anna , Born Sebastian , Maier Lars , Schweda Frank , Wagner Stefan
Published: November 2024

Background and Purpose:
Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function.

We hypothesized that Empagliflozin treatment improves left ventricular ejection fraction (LVEF) independent of diuretic effect of renal SGLT2 inhibition.

Methods:
We evaluated NTproBNP, hematocrit, hemoglobin and bodyweight in patients with HF with reduced (n=32) and preserved ejection fraction (n=59) after 30 and 180 days (prospective, single-arm CINNAMON-study, DRKS00031101). Furthermore, we conducted transverse aortic constriction (TAC) or sham surgery in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2
-/-
). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Water intake and output was evaluated by metabolic cages at 10 weeks and cardiac function by echocardiography.

Results:
Empagliflozin treatment reduced NT-proBNP levels and increased hematocrit and hemoglobin levels especially in patients with reduced ejection fraction (Fig. A-C). Surprisingly, there was no change in body weight (Fig. D), which would be expected if the diuretic effects were dominant. In mice after 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced LVEF. Empagliflozin attenuated changes in LVEF (Fig. G) and improved diastolic dysfunction (isovolumetric relaxation time, data not shown). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and Empagliflozin prevented this deterioration similar to WT mice (Fig. G vs. I). Surprisingly, Empagliflozin did not increase drinking and urine volume neither in wildtype nor in SGLT2 deficient mice, suggesting a mechanism of cardioprotection independent of diuretic effects.

Conclusion and Outlook:
This is the first study investigating the role of SGLT2 in Empagliflozin treated patients and mice with heart failure. Importantly, empagliflozin treatment prevented deterioration of LVEF independent of the presence of SGLT2 and diuresis.