bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14354: The Impact of Riociguat in Pulmonary Arterial Hypertension Patients With Comorbidities Included in Interventional Clinical Trials
Authors: Rosenkranz Stephan , Ghofrani Ardeschir H , Hoeper Marius , McLaughlin Vallerie , Rahner Claudia , Langleben David
Published: December 2023

Background:
The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing, however, there are few published data from these patients in PAH therapy clinical trials meaning that evidence-based treatment recommendations have not been made.

Aim:
This post-hoc analysis of pooled riociguat clinical trial data assessed the impact of riociguat in patients with PAH and comorbidities.

Methods:
All interventional studies of riociguat in patients with PAH (PATENT-1, PATENT PLUS, RESPITE, MOTION, REPLACE, and the Phase II study) were included in the pooled analysis. The safety of riociguat and placebo was assessed in patients with ≥3 comorbidities vs <3 comorbidities. Safety was assessed by adverse events (AEs) and serious AEs (SAEs). Comorbidities included: age ≥65 years, body mass index ≥30 kg/m
2
, history of essential hypertension, diabetes mellitus, history of significant coronary artery disease, and atrial fibrillation.

Results:
The 609 patients who received riociguat and 132 patients who received placebo in the main phase clinical trials of riociguat were included in the analysis. Of these, 113 patients (19%) in the riociguat group and 21 patients (16%) in the placebo group had ≥3 comorbidities. In both treatment groups, AE rates were higher in patients with ≥3 comorbidities vs <3 comorbidities (riociguat 93% vs 86%; placebo 95% vs 84%); with most AEs being mild or moderate. Study drug-related AE rates were similar in both treatment groups and in patients with ≥3 comorbidities vs <3 comorbidities (riociguat 54% vs 56%; placebo 52% vs 52%). SAE rates were higher in riociguat-treated patients with ≥3 comorbidities vs <3 comorbidities (25% vs 12%); of these, 4% and 3% were study drug-related, respectively. In patients with ≥3 comorbidities, study drug-related SAE rates were higher in those receiving placebo vs riociguat (10% vs 4%). AE rates leading to study drug discontinuation were higher in patients with ≥3 comorbidities vs <3 comorbidities (riociguat 6% vs 4%; placebo 10% vs 6%), whereas AE rates leading to death were similar in both groups (riociguat 2% vs 1%; placebo 0% vs 4%).

Conclusion:
These data suggest that riociguat had an acceptable tolerability profile in PAH patients with comorbidities with most AEs being mild or moderate.
Abstract 14379: Get With The Guidelines
®
Registry Data Tools and Analysis Platform
Authors: Beon Chandler D , Mallya Pratheek , Wang Lanjing , Manchanda Vihaan , Picotte Holly , Hall Jennifer L , Zhao Juan , Feng Xue
Published: December 2023

Introduction:
The American Heart Association (AHA) Get With The Guidelines
®
(GWTG) registry has emerged as a vital resource in hospital-based quality improvement and advancing the standards and practices for inpatient cardiovascular/stroke care. The GWTG registry data, with over 13 million records collected from over 2600 hospitals, has resulted in over 600 peer-reviewed publications.

Goal:
The goals of this project were to test new technology tools, including an interactive web-based interface connected to a database in a cloud-based workspace on the
AHA Precision Medicine Platform
(PMP)
, to simplify GWTG data queries and analysis for researchers.

Methods:
A new GWTG database was built using the PostgreSQL relational database system. Integration between the database and the user interface was built using the Django web framework. Data processing and quality control was done through a series of steps including schema verification, documentation generation, and de-identification. The user interface was tested within an AHA PMP workspace that provides security, privacy, statistical analysis tools and computational power.

Results:
The interactive user interface and GWTG database will be accessible to researchers with approved manuscript proposals conducting their own analysis on the AHA PMP. As shown in the figure, the user-friendly interface allows researchers to efficiently filter large volumes of data using structured querying language or built-in filtering functions. Researchers can create the cohort needed and perform the approved analysis, leveraging the statistical tools within the secure and private workspace on the AHA PMP.

Conclusion:
The AHA is committed to the FAIR (Findable, Accessible, Interoperable, Reusable) guiding principles of data. We have launched this new technology to provide streamlined access to GWTG data, powerful analysis tools, and computational power for all researchers.
Abstract 14382: Discovery of Magnetocardiography for Monitoring of Myocardial Injury Following Radiotherapy: A Case Report
Authors: Zhang Huan , Yang Jiaxuan , yang shuwen , Liu Linqi , Zhou Shu , Yang Xueyao , Ma Zhao , Ding Ming , Cai Bin , Tu Chenchen , Liu Wen-Yang , Song Xiantao , Zhang Hongjia
Published: December 2023

Introduction:
Radiotherapy, as one of the important management approaches for cancer, could induce the cardiomyocyte injury and increase the risk for cardiovascular diseases. However, early detection and identification of myocardial damage during radiotherapy is still challenging with routine methods. Magnetocardiography (MCG), a novel way to detect feeble magnetic fields formed by electrical activity of cardiomyocytes, is highly sensitive to the diagnosis of myocardial ischemia. Here, we present a case for whom the MCG changes observed during radiotherapy for thymoma.

Case:
The patient received radiotherapy for the tumor bed in the second month after transthoracoscope enlarged thymectomy and resection of the adherent tissues, with a total radiation dose of 50Gy/20F. The mean heart dose was 20.62Gy, and the volume of heart receiving greater than or equal to 30Gy is 31.77%. Comprehensive clinical biochemistry, ECG and echocardiography were taken before radiotherapy and presented without any abnormalities in cardiac structure and function. The magnetic field angle, character of positive and negative pole at T peak were also normal in magnetic field map before radiotherapy(Figure 1A). MCG and ECG were collected every week during radiotherapy. Nevertheless, during the whole 4 weeks, no significant abnormalities were found but the shape of positive and negative pole in magnetic field map became distorted gradually compared with the initial standard ellipse in MCG(Figure1B-D). Recurrent chest pain influenced the patient in the last two weeks either, which indicates the possibility of myocardial injury.

Conclusions:
Our case showed the possible minimal myocardial injury detected by MCG in the early stage of radiotherapy, while ECG is normal throughout the therapy. Therefore, our case may provide interesting insights into the potential of MCG for early detection of radiotherapy-induced myocardial damage, which deserves further validation study in the future.
Abstract 14400: Tipifarnib Mediated Reduction of Circulating Exosomes Inhibit Pressure Overload-Induced Cardiac Remodeling and Hypertrophy
Authors: Mallaredy Vandana , Roy Rajika , Cheng Zhongjian , Gurrala Charan Thej , Joladarashi Darukeshwara , Magadum Ajit , Cimini Maria , Truongcao May , Gonzalez Carolina , Benedict Cindy , Shadangi Suprit , Garikipati Venkata N , Ibetti jessica , Koch Walter J , Kishore Raj
Published: December 2023

Circulating extracellular vesicles, including exosomes, and their content have been implicated in cardiac tissue remodeling during cardiovascular disease progression. However, their role in cardiac hypertrophy and heart failure is very limited. Therefore, we investigated the role of circulating exosomes in cardiac dysfunction and remodeling in a transverse aortic constriction (TAC) model of heart failure using a recently identified exosome biogenesis inhibitor, Tipifarnib. Ten-week-old C57BL6J male mice were randomized into three groups i.e., Sham, TAC and Tipifarnib treated (10 mg/kg) TAC (TAC-Tip). The untreated TAC mice showed a significant increase in circulating exosomes along with gradual development of cardiac hypertrophy accompanied with reduced cardiac functions and increased fibrosis. On the contrary, TAC-Tip mice showed a significant reduction in circulating exosomes and remarkably improved cardiac left ventricular functions, reduced cardiac hypertrophy, fibrosis, and systemic inflammation. Strikingly, when primary mouse cardiac fibroblast cells were treated with exosomes derived from serum of TAC mice, the fibrosis related genes expression was significantly amplified compared to those treated with exosomes from TAC-Tip mice serum. Further, systemic injections of TAC-serum exosomes in normal, uninjured mice for 8 weeks, reduced cardiac function and increased cardiomyocyte hypertrophy. Small RNA sequencing analysis of serum exosomes from TAC and TAC-Tip mice displayed an extensively differential exosomal miRNAs profile. To evaluate the crucial role of miRNA in the circulating exosomes, we selected miR 331-5p based on the most differentially expressed miR and validated its expression in heart tissue and serum exosomes of Sham, TAC and TAC-Tip mice. Functional studies showed miR 331-5p inhibited HOXC8, a critical regulator of fibrosis. Overall, our studies reveal a mechanism by which treatment of Tipifarnib in TAC mice, alters not just the exosome numbers but also circulating exosomes content including miR 331-5p that directly inhibits HOXC8 and reduces fibrosis. Thus, Tipifarnib mediated inhibition of circulating exosomes may serve as a viable strategy to prevent progressive cardiac remodeling to heart failure.
Abstract 14402: Sociodemographic Differences Among Patients Receiving Coronary Artery Calcium Scoring vs. Non-Gated Chest CT Imaging
Authors: Peng Allison W , Skye Megan , Jain Sneha S , Dudum Ramzi , Maron David J , Sandhu Alexander T , Rodriguez Fatima
Published: December 2023

Introduction:
Gated CTs are used to quantify coronary artery calcium (CAC), a strong predictor of cardiovascular risk across diverse populations. However, inequities in access to gated CTs, typically not covered by insurance, exacerbate health disparities in atherosclerotic cardiovascular disease (ASCVD) risk assessment. Artificial intelligence can quantify CAC on non-gated chest CTs.

Objective:
We sought to determine sociodemographic differences in utilization of gated CAC scans vs non-gated chest CTs to identify opportunities to improve health equity in ASCVD risk assessment.

Methods:
We extracted electronic health record data on all gated CAC scans and non-gated chest CTs from 1/1/2021 - 12/31/2022 performed at Stanford Health Care. We excluded all patients with a history of ASCVD based on ICD codes and without any primary care encounters. Statistical analyses were performed using Pearson’s chi-squared test and t-test.

Results:
Out of 32,369 total CTs in our study, 5,300 (16%) were gated CAC scans and 27,069 (84%) were non-gated chest CTs. Compared with patients who received CAC scans, those who received non-gated CTs were more likely to be older, female, Hispanic, Black, have interpreter needs, and have Medicaid insurance (
Table
). They had a greater burden of comorbidities and were more likely to have visited the emergency department (16% vs. 5%) and been hospitalized (29% vs. 2%) in the prior year. Patients who underwent non-gated CTs had higher 10-year ASCVD risk scores as compared with those who underwent CAC scans (20% vs. 11%), yet only 24% were on statins.

Conclusions:
There are significant sociodemographic differences in patients who receive CAC scans vs non-gated chest CTs, highlighting opportunities to improve equity in access to tools for cardiovascular risk assessment through quantification of CAC on non-gated CTs. This supplemental approach can identify more diverse populations with higher ASCVD risk who may benefit from preventive therapies.
Abstract 14410: Hemoglobin A1c and Major Adverse Cardiovascular Events in the VA Million Veteran Program: Evidence-Based Recommendation for Life’s Essential Eight Improvement
Authors: Nguyen Xuan-Mai T , Li Yanping , Ho Yuk-lam , Houghton Serena , Pyatt Mary , Treu Timothy M , Posner Daniel , RAGHAVAN SRIDHARAN , Gagnon David , Rahman Saad Ur , Gaziano John , Djousse Luc , Phillips Lawrence , WILSON PETER , Cho Kelly ,   VA Million Veteran Program
Published: December 2023

Background:
The American Heart Association (AHA) recently proposed the Life’s Essential 8 (LE8) score as an enhanced measurement tool for cardiovascular health. For the blood glucose metric in LE8, persons with diabetes mellitus (DM) and a hemoglobin A1c (HbA1c) <7% receive higher points (40 out of 100) and successively fewer with increasing HbA1c. However, some studies have found that having a HbA1c <6% in DM patients was associated with a higher risk of mortality, especially cardiovascular (CVD) death.

Aim:
We sought to categorize DM with HbA1c <7% into two groups (<6%
vs
. 6-6.9%) and compare their associations with risk for a major adverse cardiovascular event (MACE) to better inform DM HbA1c cut points and LE8 scoring.

Methods:
Prospective cohort study of 213,760 Veterans enrolled in the VA Million Veteran Program (MVP) (2011-2021) who had a HbA1c measurement and were free of 5 point-MACE (fatal CVD, non-fatal myocardial infarction [MI], non-fatal stroke, non-fatal heart failure and non-fatal atrial fibrillation [Afib]) at baseline.

Results:
During a mean follow-up of 4.9 years, we identified 38,151 instances of MACE, including 9,665 MI, 2,837 stroke, 5,523 fatal CVD, 16,543 heart failure, and 18,114 Afib. Compared to diabetic patients with HbA1c of 6-6.9%, diabetic patients with a very low HbA1c level (<6%) had significantly higher risk of MACE [Hazard Ratio (HR): 1.15; 95%CI: 1.09-1.21], which was comparable to diabetic patients with HbA1c of 7-7.9% [HR: 1.14 (95%CI: 1.09-1.18)]. Similar results were observed for the associations between HbA1c and risk for stroke, heart failure, Afib and fatal CVD (Figure 1).

Conclusions:
Our results confirm previous findings that a very low HbA1c level among diabetic patients was associated with a higher risk for MACE. Based on our findings, we suggest further categorization of diabetic patients with HbA1c below 7% (i.e., <6% and 6-6.9%) and subsequent adjustment in LE8 scoring (i.e., from 40 to 30 points) for HbA1c.
Abstract 14427: Subclinical Age- and Sex-Differences in Ventricular Strain in the Community: A Framingham Heart Study Cardiac Magnetic Resonance Study
Authors: Pillai Rohit , Peters Kevin , Jha Vibhav , ODonnell Christopher , Manning Warren J , Tsao Connie W
Published: December 2023

Introduction:
Myocardial strain is a measure of deformation and a marker of cardiovascular disease (CVD). The subclinical age- and sex-associations of left and right ventricular (LV, RV) strain by feature tracking cardiovascular magnetic resonance (FT-CMR) are not well established in the community.

Methods:
Framingham Heart Study Offspring cohort participants (n=1077) without prevalent CVD, hypertension, diabetes, or use of treatment for these conditions underwent 1.5T CMR. Steady-state free precession cine images spanning the entirety of both ventricles were acquired in the short-axis, 2-chamber, and 4-chamber views. Global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains were measured by FT-CMR (Circle cvi42 v.5.11.1). Comparisons among age groups (<45 years, 45-54 years, 55-65 years, and >65 years) were performed by one-way analysis of variance and between sexes by independent samples
t
-test.

Results:
Clinical characteristics, CMR measures, and LV and RV strain by age and sex for the cohort are presented in the
Table
. Across increasing age groups, we observed more favorable LV GLS, GCS, and GRS (p=0.010, p<0.001, and p<0.001, respectively). Similar trends were present for RV strain for GCS and GRS (both p<0.001) but not GLS (p=0.22). Compared with men, women had greater magnitude (more favorable) LV and RV strain values for GLS, GCS, and GRS (all p≤0.013).

Conclusions:
In this large community based study of individuals without CVD, LV and RV strains by FT-CMR were greater (more favorable) with increasing age and in women. The associations and long-term implications of these differences in myocardial mechanics between groups require further investigation.
Abstract 14432: Self-Care Clustering in Adults With Type 1 Diabetes
Authors: Matus Austin M , Matura Lea Ann , Rickels Michael R , Riegel Barbara J
Published: December 2023

Poor glycemic control in type 1 diabetes (T1D) may result in cardiovascular disease. Self-care, or the process of maintaining health through health-promoting behaviors and managing illnesses when changes are detected, may improve glycemic control and outcomes. However, self-care in T1D is ill-defined. We examined how self-care maintenance, monitoring, and management cluster in adults with T1D and identified unique characteristics of individuals within each cluster. Adults (
n
=200, 27% Black, 61% female) with T1D (median[IQR] age: 35 [22] years, T1D duration: 19 [19] years, insulin pump use: 68%) reported personal, clinical and social determinants of health (SDH; modified PRAPARE tool, scored 0-22; higher is worse) and the Self-Care of Diabetes Inventory (3 self-care scales: maintenance, monitoring, management; 1 confidence scale; scored 0-100; scores ≥ 70 are adequate). Cluster analysis was performed with self-care domains as criteria via Ward’s method. To compare clusters, Kruskal-Wallis and chi-square tests were used for continuous and categorical variables, respectively. Three self-care clusters were found and labeled: Mastery (n= 70, 70% White, insulin pump use: 63%, median [IQR] age: 41 [28] years, T1D: 22 [22] years, Self-Care Maintenance: 85.4 [10.4], Monitoring: 82.4 [8.8], Management: 72.2 [13.9], Confidence: 95.5 [11.4], SDH: 2 [2]); Inconsistent (n= 112, 75% White, Insulin Pump use: 75%, median[IQR] age: 34 [22] years, T1D: 19 [18] years, Self-Care Maintenance: 79.2 [12.5], Monitoring: 67.7 [11.8], Management: 58.3 [13.9], Confidence: 88.6 [15.9], SDH: 3 [2]); and Novice (n= 18, 39% White, Insulin pump use: 44%, median[IQR] age: 25 [9] years, T1D: 14 [10] years, Self-Care Maintenance: 53.1 [9.9], Monitoring: 52.9 [13.2], Management: 44.4 [9.7], Confidence: 64.8 [27.8], SDH: 6 [7]). Significant differences were found for age (p<.001), race (p<.01), insulin pump use (p<.05), Self-Care Maintenance (p<.001), Self-Care Monitoring (p<.001), Self-Care Management (p<.001), Self-Care Confidence (p<.001), and SDH (p<.01). No differences were found in T1D duration. Three distinct profiles of self-care were found in this sample of adults with T1D. Older patients using insulin pumps with fewer SDH risk were more likely to master self-care.
Abstract 14444: Sex-Mismatch in Heart Transplantation Confers No Additional Risk of Postoperative Outcomes Established via Two One-Sided Equivalence Testing on a Propensity-Matched Cohort
Authors: Dale Reid , Leipzig Matt , Bahatyrevich Nataliya , Pines Katharine C , Currie Maria E
Published: December 2023

Introduction:
Donor-recipient sex-mismatch in heart transplantation (HTx) has decreased since the 1990s, possibly due to conflicting findings regarding its risk. Size mismatch is known to confer risk.

Hypothesis:
Previously observed differences in outcomes between the arms of sex-matched and sex-mismatched patients were due to underlying size mismatch. Sex-mismatch confers no postoperative risks beyond that due to risk beyond those due to size mismatch.

Methods:
Patients from the UNOS database between October 1, 1987 and December 31, 2022 were analyzed; under 18 years old, multiorgan transplants, and retransplants were excluded. Cohorts were separated into male and female recipients. Propensity score matching on age, transplant year, waitlist status, donor/recipient PHM ratio, preoperative diagnosis, creatinine clearance, total bilirubin, and mechanical circulatory support was performed. Two One-Sided Testing (TOST) was performed to assess between-arm equivalence in postoperative outcomes. Survival differences were measured by the between-arm ratio of Restricted Mean Survival Time (RMST) and binary outcome differences by the Odds Ratio (OR). We set the equivalence bounds per Wellek’s strict a priori bounds of (0.66, 1.50) for OR and (0.95, 1.05) for the between-arm RMST ratio.

Results:
In the non-propensity matched cohort, there were significant differences in survival at temporal endpoints up to five years for male recipients (p<0.001) but no significant differences in the female recipients at temporal endpoints up to five years (p=0.3). In the propensity matched cohort, we found significant equivalence between arms in both male and female recipients for all outcomes (Table 1).

Conclusions:
Sex-mismatch in HTx confers no additional risk to postoperative outcomes beyond those present due to size mismatch. Increasing the acceptance of sex-mismatched donors could potentially expand the donor pool and increase female donor utilization.
Abstract 14463: Beyond Sarcomere Mutations Plakophilin-2 and Familial Hypertrophic Cardiomyopathy
Authors: Shadman Shahrad , Gasimli-Gamache Leyla , Cabrera Felicia , Luther Sarah , Shirani Jamshid
Published: December 2023

Background:
Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder with diverse clinical presentation, course and outcomes. It is commonly caused by mutations in sarcomeric genes. Non-sarcomeric gene mutations have been associated with HCM in certain metabolic and storage diseases. Pathogenic mutations in plakophilin-2 (PKP2) gene have been associated with enhanced desmosomal protein degradation and linked to arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome and dilated cardiomyopathy. We report an association between PKP2 gene mutation and familial HCM.

Case presentation:
A 65-year-old man with family history of HCM (maternal grandfather, 2 aunts and an uncle) presented with dyspnea on exertion (NYHA class II-III) and pedal edema. Echo showed severe LVH, mid-cavitary obstruction and LV apical aneurysm. Cardiac MRI confirmed findings (Figure:A and B) and additionally showed significant late gadolinium enhancement (Figure:C and D, >20% of LV myocardium). Extended ambulatory heart monitor detected frequent runs on non-sustained ventricular tachycardia. A primary prevention ICD was implanted. Genetic testing identified a pathogenic mutation [c.1237C>T (p.Arg413*)] in exon 5 of PKP2 gene resulting in premature translational stop signal and disrupted desmosomal protein plakophilin-2. Family screening (Figure:E) identified a sister with positive results who also had non-obstructive HCM (Figure:E).

Discussion:
We present a family with typical presentations of HCM and no phenotypic evidence of ARVC. This novel observation provides evidence for pleiotropic model of complex genotype-phenotype interactions through nonlinear networks. Further evidence would be needed to understand potential molecular basis of hypertrophic signaling in PKP2 gene mutation.
Abstract 14502: Contemporary Practices and Outcomes in Primary Pulmonary Vein Stenosis: A PVS Network Study
Authors: Vanderlaan Rachel D , Qureshi Athar Mahmood , Hirsch Russel , Tran Crystal , Callahan Ryan , Yung Delphine , Austin Eric D , Handler Stephanie S , Kalfa David M , Backes Carl H , Pizarro Christian , Prieto Lourdes R , Mohammad Nijres Bassel , Domingo Liezl , Trucco Sara M , Petit Christopher J , Baird Chris , Bansal Manish , Vorhies Erika , Overman David M , Hossain Alomgir , Rome Jonathan J , Day Ronald W , Ivy Dunbar D , Caldarone Christopher A
Published: December 2023

Background and Study Aim:
Pediatric pulmonary vein stenosis (PVS) remains a disease associated with high mortality, with studies primarily limited to single center reports. Using the PVS Network Registry, we report on contemporary practices and outcomes for a large cohort of children with primary PVS across North America.

Methods:
Children with a diagnosis of primary PVS (congenital, normal pulmonary venous connections) in the retrospective PVS Network Registry (2009-2019, n=600, 19 institutions) were analyzed using descriptive statistics, survival analysis and Cox regression analysis.

Results:
In the PVS Network Registry cohort, 393 patients had a diagnosis of primary PVS. In the primary PVS cohort, 199 (50%) were male, 105 (27%) had a genetic diagnosis and 192 (49%) were premature (median 29 (22-37) weeks). Medical therapies were used in 53(14%) patients, with Imatinib being most common (58%). Pulmonary hypertension medications were used in 182 (46%) patients, with sildenafil most reported (90%). Surgical and catheter-based interventions for PVS were performed in 334 (85%) patients. 203 (60%) patients had at least one PVS surgery and 231(71%) had at least one PVS catheter intervention. At the time of first procedure for PVS, 133 (39%) had bilateral disease, while 100 (30%) had ≥3 pulmonary veins involved. The median age was 0.54 years (IQR 0.91). Catheter based interventions were more common on the left PVs (60%). Repeat procedures were common (53%) with the majority being catheter reinterventions (78%), with an average of 3.24 (±2.75) catheter procedures per patient. The overall survival for children with primary PVS was 76% and 71% at 1 and 2 years. In children with ≥4 veins involved, survival was 59% and 52% at 1 and 2 years. Older age at intervention was protective (HR 0.66, P<0.02), while ≥3 vein involvement was associated with poor outcome (HR 1.8, p=0.05).

Conclusion:
This is the largest primary PVS cohort reported and demonstrates overall 1 year survival of 76%, however, children with multivessel disease remain at high risk. Reinterventions are common, with many undergoing repeat catheterization procedures in our cohort. The PVS Network retrospective cohort provides insights into clinical practices and will provide benchmarking for future studies.
Abstract 14517: apoE Receptor-2-R952Q Variant in Macrophages Potentiates Hyperlipidemia and Atherosclerosis in LDL Receptor-Knockout Mice via Increased Secretion of Soluble LDL Receptor-Related Protein-1
Authors: Turkson Vanessa M , Haller April , Jaeschke Anja , Hui David Y
Published: December 2023

Introduction and objective:
Apolipoprotein E Receptor-2 (apoER2) is a type I transmembrane receptor in the LDLR family expressed in vascular smooth muscle cells (VSMC), endothelium, and macrophages. An apoER2 mutation referred to as apoER2-R952Q (R952Q) is associated with elevated plasma triglyceride levels and increased risk of premature coronary artery disease and myocardial infarction in humans. This study investigated the role of the R952Q mutation of apoER2 in modulating disease development.

Methods and Results:
We generated R952Q-expressing mice using a CRISPR-directed approach. This mouse line was crossed with the LDLR knockout mouse line and the progenies were fed a high cholesterol diet for 16 or 24 weeks. Results showed that unlike apoER2 knockout, the accelerated atherosclerosis R952Q variant mice exhibited was linked to increased plasma lipid levels. Considering apoER2's expression, which is notably absent in hepatocytes, we investigated the impact of R952Q myeloid cells on disease progression via bone marrow transplant. Results showed that wildtype apoER2 mouse recipients of R952Q bone marrow recapitulated the elevated plasma lipid level phenotype while R952Q mouse recipients of wildtype apoER2 bone marrow did not. Due to the absence of LDLR in our model, we investigated LRP1’s role in the context of myeloid-specific R952Q and found an increase in the production of hypercholesterolemia-associated soluble LRP1 (sLRP1) in the plasma of high cholesterol diet-fed mice with myeloid-specific R952Q. sLRP1 may compete with cell-surface LRP1 in lipoprotein clearance, suggesting a novel mechanism by which the R952Q mutation in macrophages may increase plasma lipid levels, thereby accelerating atherosclerosis.

Conclusion:
The R952Q mutation in apoER2 accelerates atherosclerosis via overproduction of soluble LRP1, a gain-of-function mechanism in macrophages resulting in hypercholesterolemia.
Abstract 14525: Mapping Disparities in Use of Guideline-Directed Medical Therapies for Heart Failure Patients With Reduced Ejection Fraction
Authors: Desai Rishi , Stonely Danielle , ikram naira , Levin Raisa , Bhatt Ankeet , Vaduganathan Muthiah
Published: December 2023

Introduction:
Current guidelines recommend simultaneous or rapid sequence initiation of multidrug guideline-directed medical therapy (GDMT) classes for heart failure with reduced ejection fraction (HFrEF). Despite this, well documented gaps in implementation exist; however, little is known regarding geographic disparities at the county level.

Methods:
A cohort study was conducted using Medicare claims (2013-2019). Patients from the study cohort were assigned to counties based on their residential ZIP codes. County level triple therapy use- defined as simultaneous prescription fills for beta blockers, renin-angiotensin system inhibitors (RASi), and mineralocorticoid receptor antagonists (MRAs), within 90 days of a medical encounter where HF was recorded- were calculated as %s. Features of counties including area-level indicators of poverty, employment, and educational attainment and aggregated patient-level sociodemographic and medical history variables were compared by quintiles of triple therapy use.

Results:
304,857 patients from 2,600 counties were included. The median (interquartile range [IQR]) for three drug therapy use was 14.3% (10.3%-18.8%) across included counties with a wide variation (range: 0% to 54.5%). Counties in the lowest quintile of triple therapy use were concentrated in the South. Compared to counties in the highest use quintile, counties in lowest triple therapy use quintile had worse area-level indicators of socioeconomic status and were more frequently rural. Among patient-level sociodemographic factors, counties in lowest quintile had higher proportion of Blacks and patients with low-income subsidy.

Conclusion and Relevance:
Simultaneous use of three GDMT classes was infrequent in patients with HFrEF and a marked variation across counties was observed correlating with indicators of socioeconomic disadvantage. Addressing implementation gaps in GDMT use is a pressing need that requires urgent attention.
Abstract 14526:
CREG1
Deletion Inhibits Autophagy and Causes Cardiomyocyte Damage Under Nutritional Stress
Authors: Pepe Russell J , Qi Yanmei , Lee Leonard Y , Li Shaohua
Published: December 2023

Introduction:
The cellular repressor of E1A-stimulated genes 1 (CREG1) is a small, highly conserved glycoprotein ubiquitously expressed in mammalian tissues. It localizes in the endosomal-lysosomal compartment and promotes lysosome biogenesis and acidification. The goal of the current study was to elucidate the physiological function of CREG1 in the mouse heart.

Hypothesis:
We hypothesized that deletion of
Creg1
would result in pathological cardiac remodeling following nutritional stress.

Methods:
We generated whole-body and cardiomyocyte-specific

Creg1
KO

mouse lines via mating

Creg1
fl/fl

mice with
UBC-Cre-ERT2
and
Myh6-Cre
mice, respectively. Mice were fasted for 16-40 hours, and hearts were evaluated by H&E staining, immunofluorescence, electron microscopy, and biochemical analysis. Knockout mice were compared to within-litter controls.

Results:
Under ad lib feeding, some whole-body knockout mice exhibited myofibril disarray and irregular nuclei in the heart. After prolonged fasting, both whole-body and cardiomyocyte-specific deletion of
Creg1
resulted in significantly increased intracellular vacuoles, pale cytoplasm, and loss of nuclei in the papillary muscles and interventricular septa (
Figure 1
). Immunofluorescence staining demonstrated significantly increased size and number of LC3 puncta (an autophagosome marker), and Western blot demonstrated accumulation of LC3II in the

Creg1
KO

hearts. In

Creg1
KO

cardiomyocytes, electron microscopy revealed condensed and irregular mitochondria, which lost their registry with myofibers. In addition, mitophagy was impaired and sarcomeric Z-discs were either damaged or obliterated.

Conclusion:
CREG1 protects the heart from nutritional stress-induced injury, likely through the promotion of autophagic flux.
Abstract 14531: Higher Urban Health Index is Associated With Lower Ambulatory Blood Pressure in People Living in Southeast United States
Authors: Wang Zhidong , Dai Dajun , Xu Hongyan , Stauber Christine , Dong Yanbin , Zhu Haidong
Published: December 2023

Introduction:
Hypertension is common in the Southeastern (SE) United States (US), which increases the risk of heart attack, stroke and other serious health problems. Ambulatory blood pressure (ABP) monitoring is the gold standard for diagnosing hypertension and provides better information on cardio- and cerebrovascular risk than office blood pressure (BP). However, the role of social determinants of health (SDOH) and their influence on BP elevation has been scarcely examined on a neighborhood level. The Urban Health Index (UHI), developed by the World Health Organization, has the potential to measure disparities in SDOH at the small areal level and examine inequalities in health outcomes.

Hypothesis:
Higher UHI is associated with lower blood pressure.

Methods:
We analyzed data using a longitudinal cohort established in 1989 with 724 individuals (age 5-16 in 1989, 50.8% females, 47.1% African Americans) from the Central Savannah River Area. A census tract level UHI was calculated using indicators of employment, income, and educational attainment. The UHI is a unitless and continuous measure (between 0 and 1). The relationship between UHI (2000 and 2010 data) and ABP was examined using a linear regression model, adjusted for age, sex, race, and family socioeconomic status.

Results:
Higher UHI was associated with lower ABP, with a 3.15 mmHg and 2.72 mmHg drop in 24-hour systolic and diastolic ABP with 1 unit increase in UHI, respectively (2000 data; p=0.010; p=0.020). The 2010 data showed similar trends, with an increase in UHI linked to a 2.66 mmHg decrease in mean 24-hour systolic ABP (P=0.042), with the diastolic ABP reduction (1.74 mmHg) in the same direction though not statistically significant (p=0.088).

Conclusions:
This is one of the first studies to delineate the correlation of ABP with UHI. Our results show that a higher UHI is associated with lower systolic and diastolic ABP, underscoring the influence of aggregate indicators of SDOH on individual health outcomes. Our results support the utility of the UHI as a tool to inform health policymakers on disparities on a sub-county level thereby informing targeted interventions to address these disparities.
Abstract 14536: Pulmonary Vein Thrombosis: Illuminating the Risk Factors and Sequelae of a Rare and Often Incidentally Diagnosed Pathology
Authors: Sykora Daniel , Churchill Robert , Hodge David , Callori Steven , Houghton Damon , McBane Robert D , Wysokinski Waldemar E
Published: December 2023

Introduction:
Pulmonary vein thrombosis (PVT) is often diagnosed incidentally but data on its management and outcomes are sparse.

Methods:
We queried our institutional health record to identify patients ≥18 years of age diagnosed with PVT. Demographics, medications, risk factors, diagnostics, treatment, and sequelae were collected by manual chart review. Suspected tumor thrombus cases were excluded.

Results:
Seventy-two patients with PVT were identified (median age 62 years, 50% male). The cohort was mostly white (85%), overweight (BMI 26 kg/m), with frequent comorbidities including hypertension (44%), hyperlipidemia (38%), atrial fibrillation/flutter (29%), and history of venous thromboembolism (21%). The most common PVT risk factors were active malignancy (54%), lobectomy (21%), surgery within 30 days (19%), and extrinsic vein compression (15%). Most PVT were diagnosed by CT (86%) and affected a single vein (86%), mostly commonly the left upper PV (32%). Laboratory studies revealed median platelet count 243 х 10
9
cells/L (n=58) and D-dimer elevated in 6 patients when measured (67%, n=9). About one-third of patients were on therapeutic anticoagulation (37%) at PVT diagnosis. Most patients were started on new anticoagulation (78%, n=56), with unfractionated heparin as the most common initial therapy (68%). Of those anticoagulated, few were treated with a limited duration (20%, n=11, median 54 d, IQR 95) while most received indefinite anticoagulation (80%, n=45), primarily warfarin (45%), apixaban (24%), or enoxaparin (21%). Serial imaging was obtained in 69% (n=50, median 65 d, IQR 116) and demonstrated resolution of PVT in 32 (64%) patients. Common PVT complications noted were as follows: 4 year risk of LA thrombus (26%, 12/16 anticoagulated), mechanical ventilation (13%), pneumonia (9%), and ischemic stroke (9%, 5/6 anticoagulated).

Conclusions:
PVT is often associated with active malignancy, lobectomy, recent surgery, and extrinsic vein compression. Most PVT resolve on serial imaging. Clinicians should be aware of potential high-risk sequelae including LA thrombus and stroke as well as high anticoagulation failure rates when managing PVT.
Abstract 14560: Diabetes Mellitus and Hypertension Subtypes in Relation to Cardiovascular and All-Cause Mortality
Authors: Jones Jeffrey E , Tang Kevin S , FAN WENJUN , Wong Nathan D
Published: December 2023

Background:
Diabetes mellitus (DM) is associated with increased arterial stiffness indicated by isolated systolic hypertension (ISH). Whether this relates to greater cardiovascular disease (CVD) mortality remains unclear. We compare by DM status the association of hypertension subtypes with CVD and all-cause mortality.

Methods:
We included data from the National Health and Nutrition Examination Survey 1999-2008 with mortality follow-up until 2018. We used systolic and diastolic blood pressure cut points of 130 and 80 mmHg to define ISH, isolated diastolic hypertension (IDH), and systolic diastolic hypertension (SDH) with DM based on self-report, glucose ≥126 mg/dL if fasting or ≥200 mg/dL if non-fasting, use of DM medications or insulin, or HbA1c≥6.5%. The incidence of CVD and all-cause mortality was examined among hypertensive subtypes (vs. normotension) using Cox regression, adjusting for age, ethnicity, gender, tobacco use, dyslipidemia, and use of antihypertensive agents.

Results:
23,198 individuals (projected to 194 million) were included of which 14% had DM (projected to 19 million). In those with vs. without DM, 40% vs. 60% were normotensive, 5% vs. 9% had IDH, 39% vs. 18% had ISH, and 16% vs. 13% had SDH (p<0.001). Adjusted analyses showed increased risk of CVD and all-cause mortality with ISH and IDH in patients with and without DM. IDH was significantly associated with increased CVD and all-cause mortality in individuals with DM but not in individuals without DM (p<0.0001 for interaction comparing the relation of subtypes with mortality endpoints by DM status).

Conclusions:
All hypertension subtypes were significantly associated with increased CVD and all-cause mortality in patients with DM, whereas in patients without DM only ISH and SDH carried increased mortality risk. The strength of association was also significantly greater in patients with DM.
Abstract 14592: Sepsis Cardiac Edema Related Reversible Injury (SCERRI)
Authors: Ford Verity J , Applefeld Willard N , Wang Jeffrey , Sun Junfeng , Feng Jing , SACHDEV VANDANA , Sidenko Stanislav , YU Zu-Xi , solomon steven B , Solomon Michael A , Chen Marcus Y , Natanson, MD Charles
Published: December 2023

Background:
In human septic shock, radionuclide cine angiograms found depression of LVEF and dilatation of the LV (EDV). Peaking at 48h after shock onset, the changes reversed by day 10. Nonsurvivors paradoxically had normal EFs and EDVs. Subsequent TTE studies have not consistently reproduced these findings. To investigate this paradox, we reviewed published clinical studies of cardiac function during sepsis and performed serial CMRIs in a canine model of sepsis-induced cardiac changes.

Methods:
Clinical studies of sepsis reporting EFs and EDVs in survivors and nonsurvivors were identified from 1980 onward. Sedated purpose-bred beagles (25, 2 y/o) intra-bronchially challenged with
S. aureus
or saline had serial CMRIs and histology.

Results:
Mean EF at 24h ranged from 31-69% across 20 clinical studies. Over these studies survivors
vs.
nonsurvivors, mean EF differences were only 1% (p=0.15; I
2
5%). Twelve clinical sepsis studies reported mean EDVs and showed that survivors had larger EDVs than nonsurvivors (SMD 0.36, p<0.0001; I
2
57%). Like clinical studies, EFs in our
S. aureus
challenged animal model was similarly depressed in both survivors and nonsurvivors (41% vs. 45%, p=0.34). In animals like humans, LV EDV was significantly higher at 48h in survivors
vs
. nonsurvivors (40 vs. 30 ml p=0.02) while CVPs and PAOPs were similar throughout (p=ns). From 48 to 96h the septic animals EF recovers towards normal in survivors. CMRIs in septic animals
vs.
controls showed LV wall thinning with a progressive significant loss of dry mass (~ 1g/24h over 96h) and increased LV wall edema (2-4% total over 96h). There was no histological or biochemical evidence of myocyte necrosis, elevated troponins or BNPs, only endothelial and myocyte edema with mild myofilament loss.

Conclusions:
Septic shock results in ventricular wall changes not explained by loading conditions or myocardial necrosis. Sepsis-induced cardiac injury is associated with edema as demonstrated by both histopathology and CMRI. The unexpected, acute loss of LV dry mass occurred even as edema increased and the EF recovered, consistent with an adaptive, reparative process. Determining how dry mass is lost and which cells and tissues are affected may clarify mechanisms of cardiac injury and repair in septic shock.
Abstract 14597: Beyond Sex Bias: The Uncharted Role of Rage Signaling in Pulmonary Arterial Hypertension
Authors: Lawal Odunayo S , Niihori Maki , McClain Nolan , James Joel , Rafikov Ruslan , Rafikova Olga
Published: December 2023

Background:
Pulmonary arterial hypertension (PAH) is a life-threatening disease that initiates in response to pulmonary artery endothelial cells (PAEC) damage followed by inadequate repair. The Receptor for Advanced Glycation Endproducts (RAGE) triggered upon the damage, plays a crucial role in vascular regeneration. However, its specific impact on PAH remains incompletely explored.

Hypothesis:
In this study, we investigated the sex-specific outcome of RAGE deletion on PAEC homeostasis.

Methods:
The effect of the global RAGE knockout (KO) on pulmonary hemodynamics, cardiac and endothelial function was studied disaggregated by sex in WT and RAGE KO rats. Endothelial integrity was evaluated via the expression of endothelial junction proteins, the activity of barrier disruptive signaling pathways, and in vivo pulmonary vascular permeability assay. To understand the significance of diminished RAGE signaling in male PAH, we measured membrane RAGE levels in untreated and Sugen/Hypoxia treated rats of both sexes and examined the publicly available single-cell transcriptomic profiles of human PAECs.

Results:
Male but not female RAGE KO rats developed a spontaneous PAH characterized by a significant increase in the right ventricle (RV) systolic pressure and RV hypertrophy. The PAH phenotype in males corresponded with a male-specific decrease in the expression of CD31 (WT vs. RAGE KO: 1.0 ± 0.07 vs. 0.1 ± 0.02, p <0001, N=6), activation of p38/RhoA signaling axis (p-p38 in WT vs. RAGE KO: 1.0 ± 0.2 vs. 3.2 ± 0.6, p=0.01, N=4), significant PAEC cytoskeletal rearrangement, and increased FITC-dextran extravasation, while female RAGE KOs remained unaffected. We also discovered that Sugen/Hypoxia treatment induced a substantial loss of membrane RAGE, specifically in males. Additionally, human PAEC transcriptomic data revealed that RAGE is expressed primarily in young females but not in males or older females.

Conclusions:
We conclude that the male sex associates with a reduced RAGE expression and signaling in PAEC, which is further diminished in PAH. The disruption in RAGE signaling, in turn, impairs the pulmonary endothelial barrier, instigates spontaneous PAH, and may contribute to the more severe phenotype observed in male PAH patients.
Abstract 14601: Increased Risk of Major Adverse Cardiovascular Events Attributed to Lipoprotein(a) Across Current Atherosclerotic Cardiovascular Disease Risk Categories
Authors: Benbow Harriet , Al Zabiby Anas , Hu Xingdi , Byrne Hannah , Costa-Scharplatz Madlaina
Published: December 2023

Introduction:
AHA guidelines recommend measurement of lipoprotein(a) [Lp(a); an inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD)] in individuals with a family or personal history of premature ASCVD. Lp(a) measurement is also recommended for recalibrating the 10-year risk score for borderline or intermediate risk individuals. However, there is limited evidence on the risk of MACE attributed to elevated Lp(a) across ASCVD risk categories.

Hypothesis:
To assess the impact of elevated Lp(a) levels on MACE across ASCVD 10-year risk categories.

Methods:
This observational, retrospective study included a primary prevention cohort of Caucasian and Black ethnicities from the UK Biobank (2006-2020). Associations of Lp(a) level (categories of 105-150, 150-190, 190-215, and 215-260 nmol/L were compared to Lp(a) <105 nmol/L) with time to first MACE and MI were assessed using Cox proportional hazard models adjusted for age, sex, and ethnicity, stratified by ASCVD 10-year risk score category.

Results:
The cohort (N=362,061) included 55.2% female, 94.3% Caucasian and 1.6% Black. MACE incidence rates (IR, per 100 person/years) increased with 10-year ASCVD risk score: low risk IR=0.14 (n=161,183), intermediate risk IR=0.72 (n=121,272) and high-risk IR=1.52 (n=27,733). Within and across these risk categories, elevated Lp(a) conferred a significant increase in risk of MACE and myocardial infarction (MI). In the low-risk category, HRs ranged from 1.15-1.55 (MACE) and 1.32-1.72 (MI), in the intermediate risk category HRs ranged from 1.19-1.51 (MACE) and 1.37-1.77 (MI), and in the high-risk category HRs ranged from 1.12-1.55 (MACE) and 1.14-1.76 (MI) (Figure 1).

Conclusions:
Our study demonstrates that elevated Lp(a) increases the risk of MACE independently of ASCVD risk score. Measuring and considering elevated Lp(a) levels as part of individual ASCVD risk assessment in routine clinical practice may help improve the risk predication.