bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4143378: Polygenic Risk Stratification for Risk of Venous Thromboembolism: Analysis of >31K Individuals from the Women’s Genome Health Study and JUPITER trials
Authors: Rosamilia Michael , Marston Nicholas , Melloni Giorgio , Kamanu Frederick , Sabatine Marc , Ruff Christian , Ridker Paul , Chasman Daniel
Published: November 2024

Introduction:
Venous thromboembolism (VTE) carries high morbidity and mortality, highlighting the importance of early risk identification and prevention. Whether a recent polygenic risk score (PRS) could help identify those at highest risk in a longitudinal, primary prevention population is unclear.

Hypothesis:
PRS is an independent predictor of VTE risk in a primary prevention population.

Methods:
We applied the 2023 VTE PRS by Ghouse et al containing over 1 million VTE-associated SNPs to 2 primary prevention trials, JUPITER and Women’s Genome Health Study (WGHS). We calculated the adjusted hazard ratio (aHR) of VTE per 1 higher standard deviation (SD) of PRS and by risk categories: low (bottom 20%), intermediate (middle 60%), and high (top 20%) in a multivariable model adjusted for cardiovascular and demographic factors.

Results:
JUPITER included 8,749 participants (67.8% men, median age 66) with a median follow-up of 2.3 years and 77 VTE events (annualized event rate [ER] 0.38%). WGHS included 22,650 women (median age 53) with a median follow-up of 20.5 years and 618 VTE events (annualized ER 0.13%). Each SD increase in VTE PRS was associated with a 34% higher risk of VTE in JUPITER (aHR 1.34, 95% CI 1.08-1.67; p < 0.01) and a 61% higher risk in WGHS (aHR 1.61 (1.5-1.73; p < 0.01). Those in the high PRS category were 3.3-fold more likely to develop VTE compared to those with low PRS (JUPITER: aHR 3.30, 1.38-7.88; p
<
0.01 and WGHS: 3.27, 2.44-4.38; p < 0.01) (
Fig A, B
). In comparison, Factor V and prothrombin gene mutations were associated with aHRs of 1.58 and 2.45 in JUPITER and 1.42 and 1.75 in WGHS, respectively. Additionally, the PRS predicted VTE to a similar or greater degree than established clinical risk factors. Finally, Kaplan-Meier curves demonstrated early and sustained separation in VTE events between each PRS risk group (
Fig C,D
).

Conclusions:
In two large primary prevention cohorts, PRS was a strong and independent predictor of VTE, with the top 20% imparting greater risk than that of established monogenic thrombophilia.
Abstract 4143384: High Accuracy Diagnostic of 4-Electrodes-12-Leads-Wearable-Smartphone-Based-Electrocardiogram(ECG)-System Tracing in Patients with ST Elevation Myocardial Infarction Compared to Standard ECG Tracing. AngelUS® STEMI Study
Authors: Castagna Marco , Nuic Katia , Abreu Bernardo , Ornelas Carlos , Toledo Campo Dall Orto Frederico , Ilene Castagna , Aguiar Fabiana , Cavalieri Mauricio , Miranda Rene , Assis Thiago , Teixeira Caiser , Aparecida da silva Pricylla , Pereira Wille Dingsor , cheneau edouard , Ramos Daniel , Baldo Marcelo , Ajani Andrew
Published: November 2024

Introduction:
ST elevation myocardial infarction (STEMI) is associated with a persistent high global mortality rate. Early diagnosis and treatment are essential to improve cardiac outcomes. Wearables may play a key role as promising technology in this clinical scenario.

Methods:
70 consecutive patients were referred to coronary angiography (cath) due to typical chest pain and STEMI standard 12-lead ECG tracing. At cathlab, 4-electrodes-12-leads-wearable-smartphone-based-ECG-System(AngelUS®) tracing was performed. ECG tracings interpretations were compared between the 2 groups by independent cardiologists blinded to ECGs and then correlated with cath findings. The Cohen κ statistic was used to measure agreement between the 2 groups.

Results:
Both cardiologists agreed to include 70 standard ECG tracing and 70 AngelUS® ECG tracing as STEMI. Both cardiologists agreed to exclude 70 standard ECG tracing and 70 AngelUS® ECG tracing as absence of STEMI, showing a perfect agreement with Cohen’s k:1. Correlations with coronary angiography were also performed showing total agreement with both ECG diagnostics.

Conclusion:
In 70 consecutive patients with typical symptoms and STEMI, standard ECG and the AngelUS®4-Electrodes-12-Leads-Wearable-Smartphone-Based-ECG showed clinical agreement. Correlations with coronary angiography were also performed, showing clinical equivalence between both ECG diagnostics. Analysis of AngelUS® ECG tracing compared to standard ECG is ongoing, extending our investigation into the utility of this technology in preoperative ECGs.
Abstract 4143390: HEMODYNAMIC AND CLINICAL IMPACT OF OBESITY IN GROUP 1 PULMONARY HYPERTENSION
Authors: Varma Revati , Kabbara Allababidi Adel , Reddy Yogesh
Published: November 2024

Introduction:
Obesity is rising in prevalence worldwide and co-exists in patients with group 1 pulmonary hypertension (PH). Clinical and hemodynamic implications of having obesity in group 1 PH remain unknown.

Hypothesis
. We hypothesized that obese patients with group 1 PH would exhibit worse hemodynamic parameters including higher right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) compared to non-obese patients.

Aims:
To compare hemodynamic parameters obtained from right heart catheterization (RHC) and echo among group 1 PH with and without obesity.

Methods:
We evaluated a cohort of patients with group 1 PH who underwent RHC at Mayo Clinic Rochester between 2002 to 2021 with diagnosis adjudicated by detailed chart review and initiation of pulmonary vasodilator therapy. Patients with a mean pulmonary artery pressure (mPAP) ≥ 25 mm who were clinically diagnosed with WHO Group 1 PH and recommended pulmonary vasodilator therapy initiation were included.

Results:
Of 822 participants with group 1 PH, obesity was common, present in 325 patients (40%). There was no difference in survival among patients with and without obesity (HR 1.15; 95% CI 0.95-1.38; p=.15). Obese patients had higher RAP (12.8 ± 6.8 vs 10.4 ± 6.5 mm of Hg, p<.0001) and cardiac output (5.2 ± 2.2 vs 4.5 ± 1.8 L/min, p<.0001) compared to non-obese group (Table 1). Despite having group 1 PH, pulmonary capillary wedge pressure (PCWP) was higher with obesity (13.8 ± 6.3 vs 12.2 ± 6.5 mm of Hg, p=.001) compared to those without obesity. Along with higher PCWP, there was less pulmonary vascular disease severity with obese group 1 PH, with higher pulmonary artery compliance (PAC, 1.65 ± 1.06 vs 1.38 ± 0.84 mL/mm of Hg, p=.0002) and lower pulmonary vascular resistance (PVR, 7.9 ± 5.2 vs 9.4 ± 7.7 Wood Units, p=.0007). After accounting for age, gender, diabetes mellitus and systemic hypertension, the RAP, cardiac output, PAC and PCWP remained significantly higher, and PVR remained lower in obese patients (p<0.05 for all).

Conclusions:
Comorbid obesity is associated with higher biventricular filling pressures, higher cardiac output and lower pulmonary vascular disease severity in otherwise clinically diagnosed group 1 PH. These findings call for further study of whether targeting obesity with novel weight loss drugs such as glucagon like peptide 1 receptor agonists or other drugs can lower biventricular filling pressures and associated pulmonary hypertension in group 1 PH with obesity.
Abstract 4143420: Additive Prognostic Significance of Vascular Disease in Patients Referred for Exercise Stress Echocardiography
Authors: Hart Hannah , Omar Alaa , Argulian Edgar
Published: November 2024

Background:
The presence of carotid plaque (CP) may serve as an indicator of panvascular atherosclerosis. However, the observed incongruity between carotid disease and the presence and severity of coronary artery disease (CAD) suggests differing mechanisms. We investigated the prognostic value of this incongruity, considering both known atherosclerosis and myocardial ischemia.

Methods:
In a retrospective analysis, we examined 111 patients (mean age: 64±12 years, 58% women) who underwent exercise stress echocardiography, with recent carotid artery and coronary evaluation. We computed a Vascular Disease (VasD) score, integrating the presence of carotid plaque (CP) on carotid ultrasound, known coronary artery disease (CAD), and myocardial ischemia (MyI). Subsequently, patients were followed for 5.5 years for mortality, coronary revascularization, and cardiac hospitalization.

Results:
During the follow-up period, 29 patients experienced the combined outcome (4 deaths, 10 revascularizations, and 22 hospitalizations). Among the cohort, 44 patients exhibited no vascular disease, while 67 displayed evidence of vascular disease, categorized as 42 with VasD of 1 (comprising 30 CP, 9 CAD, and 3 MyI), 14 with VasD of 2 (5 CP and CAD, 6 CP and MyI, 3 CAD and MyI), and 11 with VasD of 3. There were no significant differences between patients with and without VasD concerning sex, diabetes, renal function, atrial arrhythmia, baseline LVEF, and baseline diastolic function. However, patients with VasD were older, had higher H2FPEF scores, and lower exercise capacity, as well as elevated baseline and exercise-induced filling pressures. The incidence of the combined outcome showed a progressive increase with higher VasD scores (p<0.001). Survival curves depicted a rising risk of the outcome corresponding to increasing VasD scores (Figure 1).

Conclusions:
The presence of vascular disease as quantified by known CAD, CP as detected by carotid ultrasound, and myocardial ischemia identified during exercise stress echocardiography demonstrates a substantial additive prognostic role in mid-term cardiovascular outcomes.
Abstract 4143443: Characteristics of patients with left ventricular aneurysms undergoing ventricular tachycardia ablation
Authors: Garikapati Srilakshmi , Maan Abhishek , Vashistha Kirtivardhan , Chadha Sakshum , Newman Seth , Mirza Jacqueline , Stanton Eric , Miller Marc , Koruth jacob , Turagam Mohit , Lampert Joshua , Whang William , Dukkipati Srinivas , Reddy Vivek
Published: November 2024

Background:
Left ventricular aneurysms (LVAs) are associated with a higher risk of occurrence of ventricular tachycardia (VT). Although there have been smaller studies and case-reports published on the role of catheter ablation of VT in patients with LVAs, larger case-series with relatively longer follow up after VT ablation are limited.

Purpose:
We sought to assess procedural characteristics and clinical outcomes after VT ablation in patients with LVAs.

Methods:
We performed a retrospective review on consecutive sets of patients with LVAs who had undergone VT ablation between 01/2015 and 10/2023 at our center. The diagnosis and segmental location of LVAs was confirmed by two independent reviewers (AM and KV) upon review of images from either a transthoracic echocardiogram or cardiac magnetic resonance imaging (cMRI). Procedural reports of VT ablation were reviewed for the characteristics of electroanatomical mapping, number and morphological features of VTs induced and ablation parameters. Data on outcomes after VT ablation was collected by using a combination of clinical follow up and data from remote monitoring and in-person device interrogations.

Results:
A total of 33 patients with LVAs underwent VT ablation at our center between 2015 and 2023. The average age of patients in our study cohort was 65 +/- 15 years and 88% of them were males. The average left ventricular ejection fraction was 34 +/- 12% and the etiology of the LVAs was ischemic in 58% and non-ischemic in 42% of patients. In the non-ischemic subgroup, the most common etiology was hypertrophic cardiomyopathy (27%) followed by other causes such as mycotic aneurysm (3%), congenital aneurysm (3%), aneurysm secondary to dilated cardiomyopathy (3%) and causes that were unclear (6%). The most common segment involved in the LVAs was apical (85%) followed by basal (in 15%) of patients. The median number of distinct VTs induced and ablated during VT ablation procedure was 2 (IQR: 1-3). The average cycle length of the VTs induced was 353 + 85 ms and the predominant morphology was right bundloid (in 77% of VTs induced).

Follow up Data: Upon a median follow up of 245 (IQR of 86-898) days, the overall success rate of VT ablation was 68%.

Conclusions:
Occurrence of VT is quite common in patients with LVAs in the setting of ischemic and non-ischemic etiologies. Our case-series describes the safety and feasibility of catheter ablation for VT in patients with LVAs.
Abstract 4143583: Impact of Heart Failure Readmission in HeartMate 3 LVAD Recipients
Authors: Tejada Frisancho Flavia , Li Zhi , Shaban Liza , Kadakkal Ajay , Hockstein Michael , Gupta Richa , Glocker Shawn , Pinilla-Vera Miguel , Rodrigo Maria , Balsara Keki , Sheikh Farooq , Lam Phillip
Published: November 2024

Background:
Despite the survival benefit of durable left ventricular assist device (LVAD) therapy in patients with advanced heart failure, hospital readmissions due to heart failure (HF) remain a significant morbidity and determinant of quality of life.

Objective:
This study aimed to characterize patients with and without a HF readmission and determine its clinical impact following HeartMate 3 (HM3) LVAD implantation.

Methods/Approach:
A single-center retrospective analysis was performed of patients who underwent HM3 LVAD implantation from January 1, 2015 to December 31, 2021. Patients with and without a HF readmission were compared based on 53 variables. Cox proportional hazard model was performed to investigate the association between HF readmission and survival.

Results:
A total of 273 patients underwent HM3 implantation. The average implant age was 58 years, 75% were men, and 78% were Black patients. Of the 273 patients, 78 (29%) had a HF readmission and 58 (74%) occurred within the first year following implant. Predictors of a HF readmission include pre-implant diabetes mellitus (HR 1.96; 95% CI, 1.2-3.2; p=0.007), pre-implant body mass index (HR 1.05; 95% CI, 1.02-1.09; p<0.001) and post implant BUN (HR 1.02; 95% CI, 1-1.04; p=0.018). There was no significant difference in survival in patients with and without a HF readmission (multivariate-adjusted HR 1.44; 95% CI, 0.87-2.37; p=0.153; Figure) at long-term follow up (6 years).

Conclusion:
Readmissions for HF remain an opportunity for improvement in the care of HM3 LVAD patients. However, a HF readmission was not associated with an increased risk of death. Addressing comorbid conditions and identifying strategies to optimize LVAD and HF management in this high-risk cohort warrant further exploration to improve clinical outcomes.
Abstract 4143624: The QTc Dilemma in Pediatric DKA: Which correction formula to use?
Authors: Medappa Maruvanda Sushmitha
Published: November 2024

Background:
In diabetic ketoacidosis (DKA), cardiac complications such as QTc interval prolongation can pose a risk for ventricular tachycardia. The Bazett formula, a standard for QTc correction, may not be the most precise for children due to a higher heart rate variability.

Hypothesis:
QTc prolongation observed in pediatric DKA is the result of heart rate overcorrection by the Bazett formula.

Methods:
A retrospective chart review was conducted on pediatric patients admitted to Saint Peter's University Hospital Pediatric Intensive Care Unit for DKA from January 2017 to April 2024. Inclusion criteria encompassed patients under 21 years with two 12-lead ECGs taken during and after DKA resolution. QTc intervals were calculated using the Bazett, Fridericia, Hodges, Framingham, and Rautaharju formulas. Electrolyte levels and pH values were collected during and after DKA resolution. Data analysis was performed using both unpaired and paired data via Stata v18.0.

Results:
The study included 34 subjects, with 7 subjects having 2 DKA admissions (n=41 ECG pairs). Unpaired analysis indicated QTc prolongation using the Bazett formula in 61% of DKA cases (p=0.015), often due to heart rate overcorrection. The other formulas did not show statistically significant QTc prolongation. Paired analysis revealed a significant QTc increase during DKA compared to the resolved state (p<0.05). Additionally, changes in ionized calcium levels positively correlated with QTc changes in DKA.

Conclusion:
While the Bazett formula often overcorrects QTc in pediatric DKA, a true QTc interval increase does occur during DKA, albeit less significantly than previously believed. The Rautaharju formula provides a more accurate correction. The Fridericia and Hodges formulas are unreliable. An increase in ionized calcium is also noted in DKA. Current pediatric DKA management guidelines should include routine 12-lead ECGs and venous blood gas analyses with electrolytes to monitor QTc changes and mitigate arrhythmia risks.
Abstract 4143635: Stress-related Sleep Disturbance Inflames Myocardial cGAS-STING Pathway through activating bone marrow macrophage
Authors: Che Xinyu , Xia Yan , Chen Ao , Chen Zhangwei , Qian Juying , Ge Junbo
Published: November 2024

Background/Introduction:
Delayed bedtime following stress disorder is prevalent in waves of pandemics and modern life. Considered to be a specific and important contributor to cardiovascular health, stress-related sleep disturbance has an unmet need in steady preclinical models. We previously found exciting corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) area of mice could induce 3-hour-long wakefulness.

Methods:
The chemogenetic method of designer receptors exclusively activated by designer drugs (DREADD) system was adopted to mimic stress-related sleep disturbance. We transfected PVH CRH neurons with rAAV-hSyn-DIO-hM3Dq-mCherry and rAAV-Crh-CRE. Prolonged CRH neuron activation was induced by daily intraperitoneal injection of clozapine N-oxide (CNO, 3mg/kg) at 9 am. Bulk RNA-sequencing and bioinformatics analysis were conducted for mechanistic exploration.

Results:
2-week repeated chemogenetic activation of PVH CRH neurons induced a 5-fold corticosterone release, consistent with increased daily 3-hour wakefulness and corresponding decreases in both rapid eye movement (REM) as well as non-REM sleep. Over 30% of chronic CRH activation mice displayed difficulties in maintaining balance and experienced premature mortality. Mice subjected to prolonged CRH activation showed impaired left ventricular ejection fraction (67.9% versus 48.2%, p=0.0011), and immune cell infiltration demonstrated by histological staining. Intriguingly, the number of circulating monocytes increased. Then, we performed bulk RNA-sequencing of heart and bone marrow from CRH-activated and control mice. Differential gene expression and gene set enrichment analysis (GSEA) indicated marked activation of interferon-beta-related pathways in both tissues. Cytosolic DNA-sensing pathway and related key effector genes (cGAS, Cxcl10, Ccl5) were found up-regulated in the heart, while the mitochondrial oxidative phosphorylation pathway was suppressed. We further adopted the CIBERSORT tool to estimate immune infiltration in heart tissues and characterized M1 macrophage as the main pro-inflammatory cell. In our stress-related sleep disturbance mouse model, macrophages in the heart and bone marrow shared similar properties inducing interferon-stimulated genes.

Conclusion(s):
Taken together, we report a failing heart in a mouse model of stress-related sleep disturbance. The neuro-immune axis involvement and molecular mechanisms merit in-depth explorations.
Abstract 4143675: The epigenetically regulated transcription factor ZBTB16 protects against cardiac aging
Authors: Wagner Julian , Stilz Kathrin , Tombor Lukas , Rodriguez Morales David , Glaser Simone-franziska , Fischer Ariane , Schmitz Katja , Yekelchyk Michail , Braun Thomas , Zeiher Andreas , Dimmeler Stefanie
Published: November 2024

Aging is a major risk factor for cardiovascular diseases contributing to the progressive deterioration of heart function. Since the vascular niche was shown to maintain cardiac homeostasis, we explored the epigenomic and transcriptional circuits driving endothelial cell (EC) impairment with aging. Analysis of chromatin accessibility by snATAC-seq and gene expression by RNA-seq of hearts from 18- to 20-month-old mice revealed a significant reduction in chromatin accessibility and expression of the zinc finger transcription factor ZBTB16, which was also confirmed in aged human hearts. Haploinsufficiency of
Zbtb16
reduced diastolic function at 3 months of age and was associated with typical hallmarks of cardiac aging, such as hypertrophy, fibrosis, decreased innervation, elevated perivascular senescence, and lower capillary density. In vitro studies confirmed the crucial role of ZBTB16 in endothelial cells. Silencing of
ZBTB16
impaired EC proliferation, migration, and network formation while inducing senescence. RNA-seq from ZBTB16-silenced EC and snRNA-seq of hearts from Zbtb16+/- mice further showed an induction of secreted senescence-associated secreted proteins and several growth factors. To assess a potential effect of ZBTB16 on the paracrine communication, we performed co-culture experiments with fibroblasts, cardiomyocytes and nerves. Indeed, supernatants of
ZBTB16
-silenced ECs induced activation of cardiac fibroblasts, while
ZBTB16
overexpression in long-term cultured ECs prevented paracrine fibroblast activation. Supernatants of ZBTB16 silenced ECs additionally induced cardiomyocyte hypertrophy and reduced neuronal sprouting. In silico ligand-receptor analysis additionally confirmed the augmented interaction of EC and fibroblasts in vivo and showed and increased PDGFB signaling between the two cell types. Neutralizing antibodies against PDGFB attenuated the effects of conditioned
ZBTB16
-repressed EC medium on fibroblasts. Using chromatin-immunoprecipitation-sequencing, we further identified ZBTB16 targets, which include the nuclear receptor-interacting protein 1, which mediates PDGFB expression and paracrine fibroblast activation.

In conclusion, ZBTB16 is a master regulator of cardiac aging. Its reduction induces a pro-inflammatory and pro-fibrotic endothelial cell secretome, which affects fibroblast, cardiomyocytes and nerves in vitro. These findings highlight the role of ZBTB16 in maintaining vascular niche functions during aging.
Abstract 4143728: Pregnancy-Associated Spontaneous Coronary Artery Dissection in the Antepartum Period: Navigating Clinical Uncertainties
Authors: Goodrich Robyn , Rodriguez-Lozano Patricia , Wang Shuo , Ondigi Olivia , Wingerter Kelly
Published: November 2024

Description of Case:
A 35-year-old G2P1 female with history of drug and tobacco use presented to the emergency department at 25 weeks of gestation with chest pain in the setting of a recent upper respiratory infection. Her vital signs and electrocardiogram (EKG) were normal; however, HS-troponin was elevated at 398 ng/L (normal <5.0 ng/L). An echocardiogram revealed a left ventricular ejection fraction (LVEF) of 55-60% and apical hypokinesis (Figure 1). The initial differential diagnosis included viral myocarditis (supported by elevated inflammatory markers), spontaneous coronary artery dissection (SCAD), and distal atherosclerotic coronary artery disease. Given her hemodynamic stability and preserved LVEF, the risk of invasive angiography outweighed the benefits. She was discharged with medical management and follow-up with maternal-fetal medicine and cardio-obstetric specialists.

She underwent planned cesarean delivery at week 37 of gestation. The following day, coronary computed tomography angiography (CCTA) revealed severe stenosis of the mid-left anterior descending (LAD) artery (Figure 2A). Hours later, she had recurrence of chest pain without EKG changes, and HS-troponin increased to 7,000 ng/L. The decision was made to proceed with invasive coronary angiography, which confirmed SCAD in the mid-LAD (Figure 2B). Revascularization was not pursued given her hemodynamic stability, and she was managed conservatively.

Discussion:
Pregnancy-associated SCAD (PSCAD) is the leading cause of myocardial infarction during pregnancy. The presented case highlights the unique challenges associated with diagnosis and management of antepartum PSCAD, emphasizing the need for a high index of suspicion in pregnant women presenting with chest pain.

In PSCAD patients, invasive angiography has been associated with an increased risk of iatrogenic dissections and may pose risks to the fetus, limiting utility. Non-invasive imaging such as CCTA may be considered in clinically stable patients; but there is limited data evaluating the diagnostic accuracy of CCTA in SCAD.

Further research is needed to elucidate optimal diagnostic and therapeutic strategies tailored to pregnant women with PSCAD, and to better understand long-term implications of this condition on maternal and fetal outcomes. Given the complexities and unique challenges of managing PSCAD, advancing understanding and developing more specific guidelines is crucial to improving care for these patients.
Abstract 4143729: PTSD-Dependent Acceleration of Aortopathy
Authors: Holman Heather , xiong Ying , Ruddy Jean Marie , Zeigler Sanford , Jones Jeffrey
Published: November 2024

Post-traumatic stress disorder (PTSD) is associated with hypertension and increased heart rate, which are risk factors for cardiovascular disease including thoracic aortic aneurysms. A connection between stress and aortopathy has been suggested, yet mechanisms linking the two remain unknown. We hypothesize that PTSD-induced mechanical signals alter thoracic aortic wall homeostasis, which can predispose to aortopathy. C57BL/6 mice underwent traumatization consisting of inescapable foot shock, single prolonged stress, and single housing. PTSD phenotype was assessed through behavioral testing for the DSM-V PTSD criteria. Group-housed control mice did not undergo the traumatization but were subjected to behavioral testing. Z-scores for each behavioral test were generated and mice with z-scores above the 85% confidence interval on all criteria were considered to have a PTSD-like phenotype. This protocol yielded a PTSD phenotype in 30% of mice mimicking the human proportion of PTSD development following a traumatic experience. PTSD mice had significantly higher systolic blood pressures (PTSD (n=10), 149 ± 7mmHg; control (n=10), 123 ± 9mmHg, p<0.05) and lower plasma renin concentrations (PTSD (n=5), 52,233 ± 4,591pg/mL; control (n=5), 80,824 ± 10,797pg/mL, p<0.05) 4-weeks post-traumatization, suggesting a PTSD-induced renin-independent hypertension. Thoracic aortae were harvested 4-weeks post-traumatization and analyzed for changes in compliance by parallel-wire myography and alterations in aortic wall structure by histology. PTSD mice had enhanced thoracic aortic wall stiffness indicating increased extracellular matrix remodeling. Thoracic aortic aneurysms (TAAs) were induced surgically (periadventitial application of 0.5M CaCl
2
to the descending thoracic aorta) at 4-weeks post-traumatization. PTSD mice had significantly larger TAAs 4-weeks post-TAA induction demonstrating an acceleration of aortopathy (PTSD (n=5), 73.9 ± 13% increase from baseline diameter; control (n=5), 29.9 ± 6.9%, p <0.05).

Our PTSD model recapitulated the human phenotype showing elevated systolic blood pressure. This hypertension is renin-independent potentially derived from alterations in neural circuits propagating a neurogenic hypertension. PTSD mice demonstrated extracellular matrix remodeling and acceleration of thoracic aortic aneurysm progression. Thus, PTSD can alter thoracic aortic wall homeostasis predisposing to or accelerating existing pathology.
Abstract 4143758: Identifying High-Risk Patients with Pathogenic Variants in
LMNA
Gene: Genome-First Approach
Authors: Krueger Seth , Matsumura Martin , Carruth Eric , Kelly Melissa
Published: November 2024

Background:
Pathogenic variants in the
LMNA
gene are associated with highly penetrant cardiomyopathy (CM), with most patients expressing the phenotype by the fourth decade. Those with
LMNA
variants are at increased risk of conduction defects or arrhythmia regardless of ejection fraction. Increased availability of genome sequencing enables discovery of
LMNA
variants in apparently asymptomatic individuals, yet data are lacking regarding the phenotypic expression profile to guide clinical management in this genome-first scenario.

Aims:
Characterize the clinical spectrum of
LMNA
phenotypes following genome screening-based identification to inform management and risk stratification.

Methods:
We screened 175,500 patient-participants with exome sequencing data in the Geisinger MyCode cohort, a healthcare-based population biobank in Pennsylvania, and identified 24 participants with pathogenic
LMNA
variants. These results have been disclosed to eligible participants through the MyCode Genomic Screening and Counseling program and referrals to genetic counseling and cardiology were recommended. From manual chart review, we abstracted: age, sex, variant consequence, lifetime cardiovascular symptoms, prior TTE, EKG and Holter data, interventions (e.g. permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD) placement), and family history. Malignant arrythmia risk was calculated using an online risk assessment tool.

Results:
Of the 24, 92% (n=22) were unaware of their variant. The median age at result disclosure was 57 years (IQR: 35-66) with 10/24 (42%) > 60 years. The most common symptoms were presyncope (58%) and palpitations (50%). Of the 24 patients, 21 had EKG or Holter data. AV Block of any degree was seen in 12/21 (57%), and 9 of the 12 (75%) received a PPM or ICD. Of the 19 patients with a TTE, 7 (37%) had an LVEF < 50%. Complete data for
LMNA
risk assessment was available for 17 patients, and 9 (53%) met
ACC/AHA/HRS
criteria for primary prevention of sudden cardiac death. Evaluation by a genetic counselor was completed in 15/24 (63%). Among the 21 patients with complete data, 10 (48%) showed a family of history of PPM/ICD, and 10 (48%) had a history of heart failure.

Conclusions:
Individuals with a
LMNA
variant identified through genome screening had high rates of cardiac dysfunction and arrhythmia consistent with clinically ascertained cohorts. These results emphasize the value of genomic screening for the identification of
LMNA
-associated CM.
Abstract 4143772: Genome wide association study meta-analysis of 19,487 individuals with mitral valve prolapse identifies 52 novel genomic regions and highlights pro-fibrosis genes
Authors: Small Aeron , Berrandou Takiy-Eddine , Georges Adrien , Morningstar Jordan , Huff Matthew , Yang Ta-Yu , Lee Jiwoo , Abner Erik , Bundgaard Henning , Wells Quinn , Wilson Peter , Cho Kelly , Rader Daniel , Ganna Andrea , Helgadottir Anna , Holm Hilma , Stefansson Kari , Gudbjartsson Daniel , Vy Ha My , Rosenberg Michael , Milan David , Borger Michael , Dieterlen Maja-Theresa , Kontorovich Amy , Engert Jamie , Thanassoulis George , Farber-Eger Eric , Gignoux Christopher , Ellinor Patrick , Peloso Gina , Norris Russell , Yu Mengyao , Bouatia-Naji Nabila , Natarajan Pradeep
Published: November 2024

Introduction:
Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation and is estimated to affect between 1-3% of the general population. A subset of individuals with MVP develop malignant arrhythmias, often in the context of myocardial fibrosis. The genetics of MVP, and genetic factors explaining why only some individuals with MVP have adverse outcomes, remains poorly understood.

Methods:
We defined MVP using a combination of claims data and echocardiographic diagnosis across 15 cohorts spanning 5 countries and performed a meta-analysis of genome-wide association studies (GWAS) for MVP including 19,487 MVP cases among 2,247,054 individuals. Causal genes were prioritized using a combination of methods including the identification of variants in active promoters/enhancers using mitral valve ATAC-seq data from an external dataset. To determine whether prioritized genes may be differentially expressed in myocardial fibrosis, we compared single-cell RNA sequencing between fibrosed papillary muscles and normal left ventricular among two individuals with severe MVP.

Results:
There were 67 unique genome-wide significant (GWS; p<5x10
-8
) genomic regions, of which 52 were novel. Of these, 38 GWS regions included either missense variants or variants overlapping a promoter active in valve tissue as suggested by mitral valve ATAC-seq data. Pathway analysis of prioritized genes highlighted etiological roles for extracellular matrix and cardiomyocyte biology. 33 prioritized genes were differentially expressed between fibrotic papillary muscle tissue and normal left ventricle, the majority of which were specific to cardiomyocytes. One of these genes,
CAMK2D
, was also observed as sub-GWS in a recent GWAS of myocardial interstitial fibrosis and has notable pleiotropy for arrhythmia traits including atrial fibrillation and atrioventricular block.

Conclusions:
We performed the largest GWAS of MVP to-date, discovering 52 novel GWS regions, and prioritized genes relevant to myocardial fibrosis, an important risk factor for adverse outcomes among individuals with MVP.
Abstract 4143840: Transthyretin V142I Genetic Variant and Heart Failure Risk: A Multi-Institutional Analysis of US Million-Veteran Program (MVP)
Authors: Sideris Konstantinos , Brinker Lina , Nelson Tyler J. , Gao Anthony , Kyriakopoulos Christos , Pridgen Kathryn , Berlowitz Dan , Tcheandjieu Catherine , Damrauer Scott , Chang Kyong-Mi , HULL LELAND , Joseph Jacob , Ferraro Jeffrey , Agiri Fatai Y. , Roblin Steven , Teerlink Craig , Stehlik Josef , Carter Spencer , lynch julie
Published: November 2024

Introduction:
Transthyretin (TTR) dissolution into monomer form and subsequent misfolding causes amyloidosis through deposition of beta-pleated sheets in end organs. Genetic sequence variations can decrease the stability of TTR leading to earlier disease manifestation, a condition known as hereditary TTR amyloidosis (hATTR). The most common variant in the U.S. - V142I, is most prevalent in individuals of African descent. We sought to explore the relationship of V142I and cardiac manifestations of hATTR, using the Million Veteran Program (MVP) dataset.

Methods:
We identified all V142I carriers in the MVP dataset who had a first visit before January 2008. Carriers were matched with controls at a 1:5 ratio based on age, sex, and race. The outcome studied was development of heart failure (HF)/cardiomyopathy (CM). Cumulative incidence and multivariable Cox proportional hazards regression models were performed to compare V142I carriers with the matched control group.

Results:
A total of 2,658 V142I carriers (3.1% of veterans of African descent in MVP) and 13,467 matched control patients were included in our final study cohort. Carriers at baseline had a median age of 53 [46-60] years, 87.2% were male, 3.5% had HF, 34.0% had type 2 diabetes mellitus (T2DM), 8.0% had bilateral carpal tunnel syndrome (BCTS), 5.2% had spinal stenosis (SS), and 19.4% had neuropathy. Patients in the control group at baseline had a median age of 53 [46-60] years, 87.2% were male, 3.4% had HF, 33.6% had T2DM, 7.9% had BCTS, 5.0% had SS, and 19.6% had neuropathy. Cumulative incidence of HF/CM at age 70, 80 and 90 years was 23.8%, 48.0%, and 68.8% for cases, and 23.7%, 40.5%, and 56.7% for controls (p=0.006), respectively
(Figure).
In a multivariable Cox proportional hazards regression model, carrier status was associated with higher incidence of HF/CM - HR of 1.13 (CI: 1.03-1.23, p=0.004). T2DM, hypertension, Charleston comorbidity index and current smoking were also associated with the outcome.

Conclusions:
We report on higher risk of developing HF/CM in V142I variant carriers compared to controls in the MVP cohort. Further research is needed to determine the most effective diagnostic and treatment approaches in veterans who may be V142I carriers at risk of developing HF/CM.
Abstract 4143858: Does Cognition Effect the Outcomes of Two Types of Virtual Cognitive Behavioral Therapy Interventions to Improve Depressive Symptoms in Patients with Cardiovascular Disease?
Authors: Thompson Jessica , Wu Jia-Rong , Chung Misook , Cha Geunyeong , Latimer Abigail , Lin Chin-Yen , Kang JungHee , Biddle Martha , Moser Debra
Published: November 2024

Background:
Depressive symptoms are prevalent in patients with coronary heart disease (CHD) and heart failure (HF) living in rural areas and are associated with worse health outcomes. Cognitive behavioral therapy (CBT) has been shown to be effective at improving depressive symptoms in patients with CHD and HF. Traditional CBT is not accessible to many rural individuals, thus alternative virtual modalities are being tested to ascertain their effectiveness. Cognitive impairment is a core feature of depressive disorders and is prevalent in up to 95% of all clinical depression diagnoses. It is unknown how cognition impacts the reduction of depressive symptoms in patients utilizing virtual CBT interventions.

Aim:
To determine if cognition moderates the impact of two different modalities of virtual CBT on depressive symptoms over a 12-month period.

Methods:
This is an on-going 12-month randomized comparative effectiveness trial. Participants with at least mild depressive symptoms were randomly assigned to CBT with either a video-conference with a therapist or a self-directed internet-based application. Depressive symptoms were measured by the Patient Health Questionnaire-9 (PHQ9) and were measured at baseline, 3-, 6-, and 12-months. Cognition was measured at baseline using two instruments, the MOCA and the Mini-Cog. Those with significant cognitive dysfunction were excluded from the study. Scores were standardized from both instruments using Z-scores and separated by the median into lower cognitive function and higher cognitive function. Repeated measures ANOVA was performed to determine whether cognitive function interacted with either intervention to produce an effect on depressive symptoms over time.

Results:
Participants (n=305) were 58±12 years old, 49% female, and had 13±3 years of education. Baseline PHQ-9 scores showed no significant difference between lower and higher cognition groups. (12±6 vs 11±5, respectively, p=.17). There was no interaction of cognition by intervention group on depressive symptoms (p=0.217). Both intervention groups had significant decreases in depressive symptoms over time (p<0.001 for time effect). There was no between-group difference in improvement of depressive symptoms (p=0.059).

Conclusion:
Both cognitive groups experience significant symptom reduction with virtual CBT, suggesting effectiveness regardless of cognitive function in rural CHD and HF patients, provided significant cognitive dysfunction is absent.
Abstract 4143880: Functional characterization of GWAS findings highlights the protective role of REST against atherosclerosis
Authors: Viskadourou Maria , Reventun Paula , Chaudhry Sharjeel , Alcharani Nunzio , Toledano Sanz Pablo , Villapudua Gastelum Carlos , Lopez-Cecetaite Gabriel , Fennell Abigail , An Roujin , Osburn William , McCallion Andrew , Battle Alexis , Lowenstein Charles , Arvanitis Marios
Published: November 2024

Introduction:
Genome-wide association studies (GWAS) have identified multiple novel loci that contribute to CAD pathogenesis, but the mechanisms of these associations remain largely unknown.

Research Question:
This study aims to functionally characterize the association between the chromosomal GWAS locus for 4q12 and CAD.

Methods:
We combined computational methods with in vitro assays and mouse models to study REST.

Results:
A meta-analysis of expression quantitative trait locus (eQTL) data and multi-trait colocalization across atherosclerosis-relevant cell types revealed that the CAD-associated 4q12 locus regulates the expression of REST, a transcriptional repressor, in human aortic endothelial cells (HAEC). This analysis identified two enhancer variants as candidate causal variants for the GWAS association. CRISPR interference confirmed that the rs6853156 variant regulates REST expression in inducible human endothelial cells. Pathway analysis in HAEC after REST silencing indicated that epithelial-to-mesenchymal transition was the most upregulated pathway. Endothelial-to-mesenchymal transition (endMT) was validated in HAEC after REST silencing, as evidenced by rt-qPCR, western blot, and immunofluorescence. Consistently, REST silencing increased endothelial permeability and migration in vitro. CUT&Tag sequencing, jointly analyzed with RNA-sequencing, highlighted L1CAM and its interactors as the most significant gene-set directly affected by REST in the endothelium. L1CAM, a known endMT activator, was expressed in HAEC only upon REST silencing and direct binding of REST to its promoter was confirmed. Simultaneous silencing of L1CAM and REST in HAEC inhibited the upregulation of mesenchymal genes and the enhanced migration induced by REST silencing. Pcsk9-overexpressing mice with an endothelial-specific knockout of Rest exhibited increased atherosclerotic plaque formation in their aortas, with increased macrophage and lipid deposition within the plaque after 16 weeks of high-fat diet exposure compared to littermate controls.

Conclusion:
In summary, our data reveal the novel role of REST in atherosclerosis as a repressor that functions to constitutively inhibit endMT and protect against atherosclerosis.
Abstract 4143932: Exploring P300/CBP as therapeutic approach for right ventricular dysfunction in PAH
Authors: Bourgeois Alice , Lemay Sarah-Eve , Grobs Yann , Theberge Charlie , Sauvaget Melanie , Martineau Sandra , Gilbert Megan , Breuils Bonnet Sandra , Potus Francois , Provencher Steeve , Boucherat Olivier , Bonnet Sebastien
Published: November 2024

Pulmonary arterial hypertension (PAH) is characterized by vascular obstruction leading to progressive elevation of pulmonary artery pressure. In the face of pressure overload, the right ventricle (RV) initially compensates (adaptive hypertrophy), but ultimately transitions to a decompensated state (marked by cardiomyocyte apoptosis and fibrosis), leading to premature death. The histone acetyltransferases P300/CBP have been identified as key pathogenic factors promoting the activation of a fetal gene program, supporting vascular remodeling in the lungs of PAH patients. Previous studies have also implicated P300/CBP in the control of pathological cardiac hypertrophy and fibrosis. However, their role in RV failure associated with PAH has never been explored. We hypothesized that P300/CBP contribute to maladaptive RV remodeling in PAH and thus represent a potential therapeutic target.

We show by Western blot (WB) and immunofluorescence (IF) that P300 expression is upregulated in compensated and decompensated RV from PAH patients, monocrotaline (MCT)- and pulmonary artery banding (PAB)-exposed rats (p<0.05), whereas CBP expression remains unchanged. RV fibroblasts (RVfbs) isolated from compensated or decompensated RV display a pro-fibrotic phenotype (increased COL, Fn, MMP and aSMA expression, WB p<0.05) associated with an increase in P300/CBP expression (WB, p<0.01).
In vitro,
pharmacological (CCS-1477) or molecular (combined siRNA) inhibition of P300/CBP decreases proliferation/survival (WB PCNA, Survivin, p<0.05) and activation (WB pSMAD2/3, aSMA, Fn, Col1, MMP2, p<0.05) of RVfibs. These effects were associated with a reduction in H3K27 acetylation (WB, p<0.05). In addition, P300/CBP inhibition prevents phenylephrine-induced hypertrophy in H9C2 cells and in isolated adult rat cardiomyocytes (IF, p<0.05). Using human precision-cut RV slices stimulated with phenylephrine and TGFb, we show that P300/CBP inhibition attenuates fibrosis [Masson’s trichrome staining (MT), p<0.05] and cardiomyocyte (CM) hypertrophy [hematoxylin and eosin staining (HE), p<0.05].
In vivo,
administration of CCS-1477 in a PAB rat model reduces fibrosis (MT, p<0.05), CM surface area (HE, p<0.01), and improves RV function (TAPSE, cardiac output, stroke volume, p<0.05).

Our finding provide evidence that targeting P300/CBP may represent a promising avenue to counter maladaptive RV remodeling in PAH.
Abstract Su1105: Healthcare Students' Attitudes on Adult Basic Life Support Training via Virtual Reality: An Exploratory Study
Authors: Fijacko Nino , Nadkarni Vinay , Abella Benjamin
Published: November 2024

Introduction:
Adult Basic Life Support (BLS) is a crucial skill for healthcare professionals. In recent years, the use of immersive technology, such as virtual reality (VR), has increased in educational research projects. However, published data have yet to show significant advantages over traditional methods for BLS education.

Research Question:
Does providing adult BLS content through VR fit the new generation of healthcare students?

Goal:
To assess student perspectives after a novel BLS educational program involving an interactive 360° VR environment.

Methods:
In June 2024, the Faculty of Health Sciences at the University of Maribor (Maribor, Slovenia) hosted 24 healthcare students from the University of Pittsburgh (Pittsburgh, USA) for an interactive 360° video-based VR adult BLS training session. The training employed Meta Quest 3 headsets (California, USA), featuring an adult BLS scenario developed by the Faculty of Health Sciences at the University of Maribor called InTECHiE360. After the VR training, the students completed a 21-question Likert scale questionnaire to evaluate their experiences, with a rating of 1 indicating "totally agree", and a rating of 7 indicating "totally disagree". Prior to the study, participants provided written consent, and data were collected anonymously to ensure confidentiality.

Results:
A total of 21 participants, with a mean age of 20 years (SD±0.7), took part in our study. The majority were female (17/21; 81%) and medical students (12/21; 57%). Most participants (16/21; 76%) had previously used VR, primarily for recreational gaming, rather than for educational purposes. The participants strongly agreed that the VR experience made them feel physically present in the adult BLS training session (mean score 1.9; SD±0.8), was realistic (mean score 2.0; SD±0.9) and provided a better learning experience compared to traditional lectures (mean score 1.5; SD±1.0). They also felt that they learned something new about adult BLS through the VR training (mean score 1.6; SD±1.1) and that adult BLS content was well presented in VR (mean score 1.4; SD±0.6). None of the participants experienced cybersickness, such as nausea or dizziness, and all of them would recommend this VR experience.

Conclusion:
We developed an interactive, immersive, evidence-based educational tool with a low risk of cybersickness, designed to appeal to the current generation of healthcare students and enhance their cognitive, behavioral, and affective learning outcomes.