bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17305: Diet-Induced Obesity Drives Phospholamban Acetylation and Promotes Cardiomyocyte Calcium Reuptake Into the Sarcoplasmic Reticulum
Authors: Mushala Bellina , Cho Ellen , Stoner Michael , Scott Iain , Robia Seth L , Manning Janet R
Published: December 2023

Background:
The rising incidence of obesity and metabolic syndrome in the US has profound implications for the pathology of heart disease in coming years. Excessive fat and sugar intake is linked to elevated acetyl-CoA, which in turn is linked to protein acetylation. Although an increasing body of work has determined that non-nuclear lysine acetylation can alter the activity and stability of key proteins involved in cardiac health, the impact of acetylation on calcium handling sarcoplasmic reticulum (SR) proteins, particularly the SERCA2a regulator phospholamban, remains poorly understood.

Hypothesis:
Metabolic dysregulation and obesity lead to the acetylation of phospholamban, relieving its inhibition on SERCA2a and increasing calcium uptake into the SR. APPROACH: C57BL/6J Mice were subjected to high fat diet-induced obesity (DIO). Left ventricle (LV) tissue was collected and analyzed using immunoblotting and acetylation was quantified by immunoprecipitation with acetyl-lysine antibodies. Human LV tissue from control and diabetic patients was similarly processed and evaluated. Adult ventricular cardiomyocytes were isolated from DIO and control mice, and DIO cells were incubated in media containing excess lipid substrates (1% Lipid Mix 1, Millipore Sigma) and acutely administered HDAC activator ITSA-1 to promote deacetylation. Changes in stimulated calcium dynamics were assessed using Fura-2AM and Fluo-4AM imaging.

Results:
Phospholamban acetylation significantly increased in LV tissue from both DIO mice (p=0.003) and human diabetic patients (p=0.034) compared to their respective controls. Primary cardiomyocytes isolated from DIO mice and incubated for 24hrs in a high-fat environment exhibited increased calcium transient amplitude and reuptake time (tau) into the SR, while incubation with pan HDAC activators significantly reduced these parameters (p=0.0004, and p=0.003 respectively).

Conclusions:
Obesity increases the acetylation of phospholamban and enhances the reuptake of calcium into the SR, while deacetylation reverses these effects. These data directly tie nutritive status to a novel phospholamban post-translational modification that may directly impact myocardial calcium handling and contractile function.
Abstract 17308: Patient and Primary Care Provider Experiences From an Implementation Study of a Risk Prediction Tool Integrating a Polygenic Risk Score and the QRISK2 Cardiovascular Risk Calculator
Authors: Fuat Professor Ahmet , Adlen Ella , Monane Mark , Coll Ruth , Little Elizabeth , Wild Jonathan , Kamali Farzan , soni yusuf , Haining Shona , Riding Helen , Giner Delgado Carla , Weale Michael E , Harrison Seamus , Donnelly Peter
Published: December 2023

Introduction:
We have previously shown that combining a polygenic risk score (PRS) for cardiovascular disease (CVD), with standard clinical risk calculators such as QRISK®2, results in improved CVD risk prediction via an integrated risk tool (CVD-IRT).

Research Question:
The objective of this study was to explore the implementation of CVD-IRT within routine practice in the UK National Health Service (NHS), through participant and healthcare provider (HCP) surveys and interviews.

Methods:
The Healthcare Evaluation of Absolute Risk Testing Study (HEART) (NCT05294419), a prospective, single-arm pragmatic trial, enrolled 836 participants undergoing health checks across 12 NHS general practices. QRISK2 and CVD-IRT scores were returned to participants via HCPs. The primary outcome of the study was feasibility of CVD-IRT implementation. This was assessed by a mixed methods approach (quantitative and qualitative methods).

Results:
After the results were reported and discussed, 520 surveys were completed by participants and 824 surveys were completed by HCPs. Subsequently, 21 participants were interviewed and 13 HCPs attended focus groups or interviews to explore their experiences. 23 HCPs completed a final questionnaire (34.8% physician, 21.7% research nurse, 43.5% other). For 90.7% of reports, HCPs indicated that the CVD-IRT could be incorporated into routine primary care in a straightforward manner. 80% of HCPs agreed that having these tests could lead to better health outcomes for patients, and 68.4% believed that the CVD-IRT could help them manage their patients through a shared decision making process covering lifestyle and treatment options. Participants found the report personally useful (98.5%) and easy to understand (94.3%); agreed that genetic measures are important to identify the risks of developing CVD (85.2%); thought that the test should be widely made available (interview summaries); and would recommend to friends and family (86.8%).

Conclusion:
The implementation of the CVD-IRT into routine health-checks was recommendable, feasible and well received by both HCPs and participants, who felt that the information was useful, could support clinical decisions, and easy to understand.
Abstract 17309: Assessing the Effect of Corticosteroid Taper Rate and Repeat Pet Imaging on Cardiovascular Outcomes Among a Homogenously Treated Cohort of Patients With Suspected Cardiac Sarcoidosis
Authors: Rojulpote Chaitanya , Bhattaru Abhijit , Adams Sarah , Salas John , Patil Shivaraj , Vidula Mahesh K , Bravo Paco E
Published: December 2023

Introduction:
Serial positron emission tomography (PET) imaging is utilized to monitor disease activity and treatment response in patients with suspected cardiac sarcoidosis (CS). However, there is no data available on the cardiovascular outcomes associated with corticosteroid taper rates and timing of repeat PET imaging in patients with CS.

Methods:
We identified 70 patients with suspected CS (Age: 56.3 ± 9, 31% female, LVEF 45.6 ± 13.6, median follow-up time: 6.3 months [4-7.6]) who were treatment naïve and displayed inflammation on baseline FDG-PET, subsequently started on a moderate-dose of prednisone only (i.e., 30-40 mg/day), and had a diagnostic follow-up PET. Patients were divided into two groups based on median follow-up time between PET scans; early (<6.3 months, n=35) or delayed (≥6.3 months, n=35) surveillance imaging. Corticosteroid taper was captured by measuring weekly changes in prednisone from treatment initiation to follow-up PET. Major adverse cardiovascular events (MACE) were defined as sustained ventricular tachycardia/ventricular fibrillation (VT/VF), heart failure (HF) admission, and death.

Results:
In this homogenously treated cohort, overall, we observed no significant difference in MACE between early vs delayed imaging groups (p=0.117, Figure 1A). Furthermore, there were no significant differences in corticosteroid taper rates between early and delayed groups (-0.927 ± 1.15 vs -0.618 ± 0.58, p=0.163). As such, we observed no difference in MACE associated with taper rate (p=0.647, Figure 1B).

Conclusion:
Patients with suspected CS undergoing repeat PET imaging had similar adverse cardiovascular outcomes despite variations in follow-up time and taper rates of prednisone. We suggest to adopt an early imaging strategy to allow for timely optimization of immunosuppression and clinical surveillance.
Abstract 17321: Cardiometabolic Risk Increased in All Socioeconomic Status During the Venezuelan Humanitarian Crisis: The EVESCAM Cohort Study
Authors: De Oliveira Gomes Diana , Nieto Martinez Ramfis , Gonzalez Rivas Juan Pablo , Babagoli Masih , Ugel Eunice , Marulanda Maria I , DURAN Maritza , mechanick Jeffrey , Danaei Goodarz
Published: December 2023

Background:
Social determinants of health (SDOH) significantly impact cardiovascular disease (CVD). Poverty is the most important underlying cause of preventable death, disease, and disability, and interacts with other SDOH. Venezuela was declared as suffering a humanitarian crisis, and besides the increase in poverty, other SDOHs such as traumatic stressors, violence, food insecurity, and treatment interruptions increased. This study aimed to estimate the changes in cardiometabolic risk factors (CMRF) in different socioeconomic statuses (SES) during the humanitarian crisis in Venezuela.

Methods:
Data from the EVESCAM Study was analyzed. The nationally-representative baseline assessment was conducted in 2014-2017 (N=3414) using a multi-stage stratified sampling and further follow-up on a subset of 35% of participants was undertaken in 2018-2020 (N=1257). Changes in CMRF and their prevalence among three SES (Low-SES N=657[52.3%], Middle-SES N=384[30.5%], and High-SES N=216[17.2%]) were compared.

Results:
There was a decrease in the prevalence of obesity (p=0.001), but an increase in the prevalence of dyslipidemia (total cholesterol ≥200mg/dL, and Low-Density Lipoprotein cholesterol ≥130mg/dL, P=0.001), low Mediterranean diet adherence (p=0.001), and depression (p=0.001) in all SES. Diabetes prevalence decreased only in middle-SES (p=0.01) and low-SES (p=0.03). Anxiety and hypertension did not change significantly. The prevalence of participants with high CVD risk (Globorisk score >20%) increased in all SES (P=0.001).

Conclusion:
There was an increase in multiple CMRF in all SES during the Venezuelan humanitarian crisis. This scenario could determine a particular pattern of morbidity determined by the interaction of several factors, including a shortage of basic goods, severe hyperinflation, and a breakdown of the healthcare infrastructure. Efforts are needed to improve the health and CVD risk of populations facing humanitarian crises.
Abstract 17322: Closing the Loop: Use of Amplatzer PFO Occluder Device in Case of LVAD-Associated Aortic Insufficiency
Authors: Betageri Omkar , Bediako Persey , Afari Maxwell E , DeNino Walter , Shah Atman , Estrada J R
Published: December 2023

Description of Case:
A 72-year-old woman with destination therapy Heartmate 3 left ventricular assist device (LVAD) presented with NYHA Class III symptoms. Review of her echocardiograms since LVAD implantation revealed progressive central aortic insufficiency (AI) with subsequent LV dilatation, managed with reduction in LVAD speed. Patient declined surgical aortic valve replacement and/or repair. After a multidisciplinary discussion, the patient opted to pursue percutaneous aortic valve closure. Cardiac CT demonstrated no aortic valve thrombus and identified appropriate anatomy for closure with an 18x25 mm Amplatzer PFO Occluder device (Graphic 1). Preoperative TEE revealed LV ejection fraction of 15% with moderate to severe AI and fibrosis of the aortic valve commissures with no aortic valve movement. The aortic valve was closed with the Amplatzer PFO Occluder with an 18mm disk that sat on the LV side of the aortic valve within the AV annulus and the 25mm disk sitting on the aortic side of the aortic valve within the sinus of Valsalva. TEE and intracardiac echocardiography demonstrated excellent device placement with two residual trace AI jets at the non-left and left-right commissure. Following LVAD speed increase, the degree of AI remained unchanged and she was discharged with improved symptoms.

Discussion:
Moderate-severe AI develops in about 15-25% of patients within 1 year of LVAD implantation. There are previous reports of LVAD-associated AI closure with an Amplatzer cribiform device. We describe the first known use of the Amplatzer PFO Occluder device for the management of LVAD-associated AI. While transcatheter aortic valve replacement (TAVR) is an attractive option to treat LVAD-associated AI, securing the transcatheter heart valve in the absence of calcifications remains a challenge.
Abstract 17339: Deficiency of Sirtuin 3 in Endothelium Reduces Endothelial-Dependent Relaxation and Impairs Myogenic Response in Coronary and Middle Cerebral Arteries of Mice
Authors: Zhang Jin , Chen Jian-Xiong , Zeng Heng
Published: December 2023

Previously, we demonstrated that specific knockout of Sirtuin 3 (Sirt3) in endothelial cells (ECs) impairs coronary flow reserve and diastolic function in mice. So far, the role of endothelial Sirt3 in the coronary arteries remains unexplored. Male and female Sirt3 EC-knockout (Sirt3 EC KO) mice and Sirt3-Lox-P mice at 14-15-month old age were used to assess the roles of endothelial Sirt3 on the microvascular functions. Mouse coronary arteries (CA) and middle cerebral arteries (MCA) were isolated and mounted in a myograph system. Myogenic response was evaluated by increasing perfusion pressure. Ach (Acetylcholine, 1nM-100μM)-induced EC-dependent vasodilation and NO donor SNP (sodium nitroprusside,1nM-10μM)-induced EC-independent vasodilation were examined. Myogenic response was significantly impaired in both CA and MCA of male and female Sirt3 ECKO mice, as evidenced by a lack of constriction while raising perfusion pressure from 10 mmHg to 150 mmHg. Both wall thickness and cross-sectional area were increased in CA and MCA of male and female Sirt3 EC KO mice. The wall to lumen ratio was increased in MCA, but did not change in CA of Sirt3 EC KO mice, compared to SIRT3-Lox-p mice. The wall tension and myogenic tone were significantly decreased in CA and MCA of both male and female Sirt3 EC KO mice. The vessel stiffness was not significantly different between SIRT3EC KO mice and SIRT3-Lox-p mice. In CA, the Ach-induced EC-dependent vasodilation was reduced in both male and female Sirt3 ECKO mice. Intriguingly, the SNP-induced EC-independent vasodilation was significantly reduced in female Sirt3 ECKO mice, but did not observed in male Sirt3 ECKO mice. In MCA, the Ach-induced EC-dependent vasodilation was only impaired in male Sirt3 ECKO mice, but was not observed in female Sirt3 ECKO mice. Whereas, the SNP-induced EC-independent vasodilation was impaired in both male and female Sirt3 EC KO mice as compared to their control SIRT3-Lox-p mice. These data revealed a sex and organ specific role of Sirt3 in EC, i.e. there is more EC-independent dysfunction in female CA, but greater impairment of EC-dependent relaxation in male MCA. Our study demonstrates the critical role of endothelial Sirt3 in maintaining microvascular function in coronary and cerebral arteries.
Abstract 17343: Coronary Microvascular Function in Physician Burnout and Job Stress
Authors: Pazhenkottil Aju P , Princip Mary , Holzgang Sarah A. A , Garefa Chrysoula , Rossi Alexia , Benz Dominik C , Giannopoulos Andreas A , Kaufmann Philipp A , Buechel Ronny R , Hackl-Zuccarella Claudia , von Känel Roland
Published: December 2023

Background:
As a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that seems more prevalent among male than female physicians.
Aim:
This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events.

Methods:
Thirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on measures of coronary microvascular function in the same model while adjusting for age and body mass index.

Results:
Burnout and job stress had significant and independent effects on endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow (MBF) response, and hyperemic MBF (r partial: 0.29 to 0.35; p-value: 0.008 to 0.027). Effort-reward ratio (r partial: -0.32 to -0.34; p-value: 0.009 to 0.017) and overcommitment (r partial: -0.29 to -0.35; p-value: 0.008 to 0.027) showed inverse associations with these measures.

Conclusions:
In male physicians, burnout and high job stress showed opposite effects on coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications. Future studies should include burnout and job stress for a more nuanced understanding of their potential impact on cardiovascular health.
Abstract 17346: The Causal Role of Obstructive Sleep Apnea (OSA) in Atrial Fibrillation (AF): A Systematic Review and Meta-Analysis of Mendelian Randomization Studies
Authors: Perera Ayodya , Gnanaguruparan Subramanian , Kodali Athri , Chenna Venkata Balaji , Mendpara Vaidehi , LAPSIWALA BONEY , Rajpopat Pratik Bharat , Gurumoorthy Rohini Bhuvaneshwari , Nair Amritha , Desai Brinda , Iermolenko Valeriia , Mondal Avilash , Desai Rupak
Published: December 2023

Background:
Atrial fibrillation (AF) causes significant morbidity and mortality. Obstructive sleep apnea (OSA) has been suggested as a risk factor for AF, but the causal relationship between the two is still being investigated. We performed a systematic review and meta-analysis of Mendelian Randomization (MR) studies to determine OSA's role in AF.

Methods:
We searched PubMed, Scopus, Embase, and Google Scholar databases for MR studies on the causal relationship between OSA and AF through June 2023. Our analysis included eligible studies. The pooled odds ratio and subgroup analysis were calculated using the random-effects model. The I2 statistic was used to assess study heterogeneity, and a leave-one-out sensitivity analysis was performed to determine how individual studies affected the overall estimate and analysis robustness.

Results:
5 MR studies met our inclusion criteria until June 2023. In these studies, one used diverse datasets and included patient data of 5 cohorts with UK, Canada, Australia, USA, Finland ancestry while the remaining 4 included patient data of European ancestry. Genetic predisposition to OSA was found to cause AF in the pooled odds ratio analysis (OR 1.21, 95% CI 1.15-1.28, I2=0.00%, p <0.01). The leave-one-out sensitivity analysis showed that the odds ratio marginally changed when specific studies were excluded, suggesting that their contribution to the estimate slightly differed.

Conclusion:
Our findings suggest a causal relationship between OSA and AF, suggesting that OSA may cause AF. The findings emphasize the need for early evaluation and treatment of AF patients with OSA. However, large-scale prospective studies are required to confirm these findings and determine their clinical practice implications.
Abstract 17355: Mitochondrial Calcium Uptake Regulates Lung Alveolar Epithelial Regeneration by Connecting Mitochondrial Metabolism With Epigenetic Changes
Authors: Ali Mir , Zhang Xiaoying , Tomar Dhanendra , Elrod John W , Tian Ying
Published: December 2023

Introduction:
Lung disease is the third leading cause of death and expanding. The endogenous regeneration of lung alveolar epithelium is severely compromised with age and chronic lung disease resulting in deaths after infections such as COVID-19. Mammalian lung alveolar epithelium consists of: alveolar epithelial type 1 and type 2 cells (AT1 and AT2). Stem/progenitor AT2 cells trans-differentiate into the gas exchanging AT1 cells in response to injury and regenerate the lost alveolar epithelium. Molecular mechanism of AT2-to-AT1 cell differentiation is unknown and its identification is critical for therapeutic development. Mitochondrial calcium controls fundamental cellular processes such as ATP production, metabolism, cell death etc. Dysregulation of mitochondrial calcium is implicated in diabetes, heart failure and neurodegeneration. Mitochondrial calcium uptake 1 (MICU1) negatively regulates mitochondrial calcium uptake which affects downstream signaling such as metabolite bioavailability and epigenetics.

Results:
We have identified a remarkable increase in MICU1 expression and a decrease in mitochondrial calcium uptake in AT2 cells during AT2-to-AT1 cell differentiation in adult mice after bacterial lung infection injury. Micu1 knockout in AT2 cells resulted in mitochondrial calcium overload, reduced AT2-to-AT1 cell differentiation and impaired lung regeneration after lung injury in mice. MICU1-dependent mitochondrial calcium regulated the citric acid cycle metabolite, α-ketoglutarate in AT2 cells. The metabolite, α-ketoglutarate, also functions as a signaling molecule and alters cellular epigenetics by activating Jumonji C domain containing histone lysine demethylases. Micu1 knockout AT2 cells exhibited α-ketoglutarate downregulation and the epigenetic change of H3K9 hypermethylation. Pharmacological inhibition of Jumonji histone demethylase in mouse AT2 cells increased H3K9me3 level and completely blocked AT2-to-AT1 cell differentiation in vitro.

Conclusions:
Overall, the results suggest that MICU1-mediated mitochondrial calcium uptake plays a key role in AT2-to-AT1 cell differentiation and lung alveolar epithelial regeneration by linking mitochondrial metabolism with epigenetics.
Abstract 17359: UCP2 Induced Glycolysis Promotes Histone Acetylation to Regulate Cardiomyocyte Cell Cycle After Injury
Authors: Pennise Jennifer L , Rigaud Vagner O , Zarka Clare , Brosious Isabella , Mohsin Sadia , Khan Mohsin
Published: December 2023

Developmental cardiac tissue is proliferative capable of robust regenerative response after myocardial injury, but this ability is lost by P7 when cardiomyocytes (CMs) exit the cell cycle and become terminally differentiated. Postnatal CMs exhibit a specialized metabolic state that supports rapid proliferation and is altered with loss of regeneration in the heart. Studies have shown that reliance on glycolysis for energy generation is preferred by proliferating CMs and activation of glycolysis promotes cardiac repair. Nevertheless, the role of glycolysis in regulating CM gene program linked to cell cycle and repair in the heart remains poorly studied. Here, we identify a novel role for mitochondrial uncoupling protein 2 (UCP2) in the heart regulating CM cell cycle dynamics. UCP2 was found to be primarily active during cardiac development, rapidly decreases after birth and is expressed at low levels in the adult heart. UCP2 overexpression in human IPS derived CMs increases cell cycle progression as assessed by immunostaining and flow cytometry-based DNA content analysis. In parallel, neonatal rat ventricular myocytes (NRVMs) overexpressing UCP2 showed increased glycolysis and glycolytic metabolites, reduced mitochondrial membrane potential and mitochondrial activity compared to controls. Next, we generated αMHC-UCPKO mice that showed reduction in total number of CMs and pHH3 levels, increased CM size and ploidy during postnatal development. Adult αMHC-UCPKO subjected to myocardial infarction injury showed significant cardiac dysfunction and fibrosis at 4 weeks compared to controls. Mechanistically, UCP2 induced glycolysis increases ATP-citrate lyase (ACLY) mediated acetyl-CoA generation in the CMs. Additionally, CMs isolated from P1 αMHC-UCPKO showed several histone modifications including decrease in histone acetylation marks. Similarly, NRVMs overexpressing UCP2 showed increased histone H3 acetylation and expression of histone acetyltransferases (HATs) and corresponding decrease in histone deacetylases (HDACs). In conclusion, UCP2 is a novel developmental metabolic regulator of CM cell cycle in the neonatal and adult heart. Moreover, UCP2 induced glycolysis increases cell cycle via altering CM histone acetylation.
Abstract 17384: Unraveling the Impact of VAMP-8 Deficiency on Atherogenesis: A Fresh Perspective on Platelet Involvement
Authors: Mohammadmoradi Shayan , Al Hawas Rania , Zhang Ming , Joshi Smita , Whiteheart Sidney W
Published: December 2023

Introduction and Objective:
Recognized for their intricate role in atherogenesis, platelets interact with oxidized low-density lipoprotein (oxLDL), immune cells, and endothelial cells and release granule proteins and microparticles, contributing to the onset and advancement of atherosclerosis. Despite the challenges of antiplatelet treatment in primary prevention, exploring alternative platelet targets could provide key insights into their role in atherogenesis. This study pivots on the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins, notably vesicle associated membrane protein 8 (VAMP-8) - the primary vesicle membrane (v-SNARE) and vital facilitator of platelet secretion.

Approach and Results:
The profound impairment in α-granule, dense granule, and lysosome release due to VAMP-8 deficiency directed our investigation towards its potential role in atherogenesis. Using RNA-seq data from washed platelets of VAMP-8-/- mice versus wildtypes, we first analyzed the molecular signature of VAMP-8 deficiency. Gene ontology analysis revealed that the major differences in enriched genes between the two groups involved triglyceride biosynthetic process and platelet calcium homeostasis. We initiated atherosclerosis studies using ApoE
-/-
mice crossed with VAMP-8
-/-
mice (n=11) alongside littermate controls (n=9), all fed a high cholesterol diet for 15 weeks. Remarkably, the deletion of VAMP-8 led to a substantial reduction in atherosclerotic lesion development when compared to the control group. Notably, this phenotype manifested irrespective of total cholesterol levels, as plasma cholesterol remained consistent across all groups.

Conclusion:
Our findings reveal that VAMP8 deficiency markedly mitigates atherogenesis, thereby proposing a novel perspective to explore the influence of platelet cargo secretion on the inception of atherosclerosis. We are currently conducting additional studies to uncover the underlying mechanisms responsible for these observations
Abstract 17415: Oxygen Uptake Kinetics at the Onset of Incremental Ramp Exercise During Cardiopulmonary Exercise Testing in Patients Undergoing Evaluation of Dyspnea on Exertion
Authors: Griskowitz Catharine , Campain Joseph , Minasian Alexandra , Prasad Cheshta , Rouvina Jennifer , White Casey , McGinnis Shaina , Kowal Alyssa , Kelly Katherine , Malhotra Rajeev , Lewis Gregory
Published: December 2023

Background:
A high metabolic cost of initiating exercise, defined by workload equivalents of unloaded cycle ergometry exercise, has been described in obese patients with HFpEF. Implications of high BMI and exaggerated metabolic cost of exercise initiation on responses to incremental ramp exercise have not been defined. We hypothesized that exaggerated metabolic cost of exercise initiation would result in delayed metabolic response to incremental ramp exercise.

Methods:
Patients underwent invasive cardiopulmonary exercise testing (CPET) on a cycle ergometer, including rest, unloaded exercise, and maximum incremental ramp exercise. Mean response time (MRT) was defined as 67% of the time to reach steady state VO
2
during unloaded exercise. On-ramp VO
2
kinetics were defined by the amount of time that it took for VO
2
to permanently increase by 5% (t
5%
), 10% (t
10%
), and 15% (t
15%
) above steady state after initiation of incremental ramp exercise. These values were adjusted for ramp and related to demographic and CPET measures by multivariate linear regression.

Results:
200 patients referred for evaluation of exertional dyspnea and suspected HFpEF (age 55 ± 16 years, 45% female, BMI of 30 ± 6 kg/m
2
, 52% HTN, 17% DM) demonstrated variability in their on-ramp VO
2
uptake kinetics after reaching steady state during unloaded exercise. Delayed VO
2
kinetic responsiveness to incremental ramp exercise, as measured by t
5%
, t
10%
, and t
15%,
was not related to age but was directly related to BMI, internal work, and prolonged MRT for VO
2
upon exercise initiation.

Conclusion:
In this initial description of VO
2
uptake kinetic patterns during the transition from unloaded to incremental ramp exercise, increased BMI, slow exercise onset VO
2
kinetics, and heightened metabolic cost of exercise initiation are all related to delayed VO
2
on-ramp kinetics. Delayed on-ramp O
2
kinetics merit further evaluation in relation to functional limitations in dyspneic patients referred for suspicion of HFpEF.
Abstract 17441: Non-Invasive Quantification of Peripheral Angioplasty-Induced Vascular Inflammation in a Porcine Model Using PET/CT Imaging
Authors: Nabavinia Mahboubeh , Rimmerman Eleanor T , Mansfield Corrin , Chou Ting-Heng , Go Michael R , Stacy Mitchel R
Published: December 2023

Background:
Similarities in peripheral vascular anatomy between swine and humans make this animal an ideal model for evaluating the effects of lower extremity angioplasty procedures commonly performed to improve limb blood flow in peripheral artery disease (PAD).

Hypothesis:
We hypothesized that PET/CT imaging would provide a non-invasive strategy for quantifying the inflammatory response to balloon overdilation injury in a swine model of peripheral angioplasty.

Methods:
Five Yorkshire pigs (weight = 25 kg) underwent overdilation of the right femoral artery. A balloon catheter (7 mm x 40 mm) was introduced via the carotid artery and guided to the femoral artery under fluoroscopy. The balloon was then inflated to a pressure 1.5 times greater the recommended nominal pressure to induce arterial injury.
18
F-fluorodeoxyglucose (FDG) PET/CT imaging was performed 14 days after angioplasty to quantify
in vivo
inflammation in the injured and control femoral arteries, which was expressed as the maximum standardized uptake value (SUV
max
). Pigs were euthanized 14 days post-angioplasty and arteries were harvested and sectioned for gamma counting (
18
F-FDG uptake), and stained with hematoxylin and eosin histology (H&E), Masson’s trichrome, and alpha-smooth muscle actin (α-SMA) for evaluation of intimal remodeling and smooth muscle cell proliferation.

Results:
18
F-FDG PET/CT imaging quantified a significant increase in inflammation for the injured versus control femoral artery 14 days post-angioplasty (p=0.04). Gamma counting confirmed a significant increase in
18
F-FDG uptake in the injured artery (p=0.02). H&E revealed a significant increase in intimal thickening in the injured artery (p=0.03). α-SMA expression was also significantly increased in the injured versus control femoral artery (p=0.01), demonstrating an increase in smooth muscle cell proliferation.

Conclusions:
18
F-FDG PET/CT quantifies arterial inflammation resulting from overdilation injury that is associated with intimal remodeling and smooth muscle cell proliferation. PET/CT imaging may provide a non-invasive strategy for
in vivo
testing of the efficacy of emerging drug-coated endovascular peripheral devices.
Abstract 17445: Near Occlusion of the Tricuspid Valve By Metastatic Melanoma
Authors: Essien Ekow , Mounir Abdulghani , Peters Matthew , Masood Faisal , Solis Joaquin
Published: December 2023

Introduction:
Metastatic tumors to the heart can have varied clinical presentations depending on location. We present a case of right atrial (RA) metastatic melanoma with near obstruction of the tricuspid valve resulting in significant hypoxia.

Case Presentation:
A 34-year-old man with a history of retinoblastoma and astrocytoma presented to the emergency department with 2 weeks of progressively worsening shortness of breath. On examination he was hypoxic and in respiratory distress. Computed tomography of the chest with contrast showed a large hypoattenuating homogeneous mass in the RA that protruded into the right ventricle and extended to the superior and inferior vena cavae. Transthoracic echocardiography (TTE) showed a large (9.1 x 4.6 cm) echodensity filling the RA and almost completely obstructing the tricuspid valve. Due to worsening hypoxia, the patient underwent palliative surgical resection of the mass. Intraoperatively, the mass was densely adherent to all walls of the RA. Surgical pathology identified the mass as metastatic malignant melanoma. The patient was started on pembrolizumab and discharged home in stable condition. At his 1-month follow-up, his symptoms had improved and he had returned to work.

Discussion:
Metastases to the heart are more common than primary cardiac tumors. Left-sided cardiac masses are commonly benign, whereas right-sided masses raise suspicion for metastatic disease. Melanoma, lymphoma, leukemia, and breast and lung cancers commonly metastasize to the heart. The size of the RA mass in this patient was significant enough to cause hypoxia and near occlusion of the tricuspid valve. Successful palliative resection of the mass resulted in a large improvement in symptoms.

Conclusion:
As the incidence of malignant melanoma increases, clinicians need to have a high index of suspicion for cardiac metastasis. Early identification of cardiac metastasis is critical as these cases can often be associated with poor prognosis.
Abstract 17446: Trends, Disparities, and Outcomes in Patients With Takotsubo Cardiomyopathy Complicated by Cardiogenic Shock
Authors: Tan Samuel , Siu Wenchy , Kumar Shasawat , Adinugraha Paulus
Published: December 2023

Introduction:
Cardiogenic shock (CS), a highly fatal complication, is estimated to be seen in up to 20% of patients with Takotsubo cardiomyopathy (TC). Previous studies have found patients with TC to have similar mortality rates as those with acute myocardial infarction, highlighting the potential importance of therapeutic intervention. However, the existing literature on TC is limited.

Hypothesis:
Minority patients with TC-CS are associated with increased mortality.

Methods:
All adult admissions with a diagnosis of Takotsubo Cardiomyopathy and cardiogenic shock (TC-CS) were analyzed using the National Inpatient Sample Database between January 2016 and December 2019. Outcomes included in-hospital mortality, in-hospital complications, and resource use. We used multivariate logistics and Elixhauser co-morbidities to adjust for clinical comorbidities.

Results:
Our study population included 37,902 patients with a diagnosis of Takotsubo cardiomyopathy. Of the sampled population, 2,455 (6.48%) experienced cardiogenic shock. Over the study time period, there was a significant increase in prevalence with TC-CS (p<0.001). Compared to patients with TC, patients with TC-CS were significantly associated with acute kidney injury (OR: 2.463, p<0.001). Controlling for baseline characteristics and Elixhauser comorbidities, Asians were at significantly higher odds of developing cardiogenic shock (OR: 1.859, p<0.001) and mortality, while Whites were at significantly decreased odds of developing cardiogenic shock (OR: 0.690, p<0.001). In addition, Asians who self-pay were at significantly higher odds (OR: 4.836, p=0.005) of developing cardiogenic shock compared with Asians holding insurance.

Conclusions:
Our study offers insights into the disparities connected with TC-CS. There is a statistically significant increase in the trend of incidence of CS among patients with TC, and CS is associated with significantly higher odds of mortality. Notably, Asian individuals with TC face significantly higher odds of developing CS. However, there were no significant differences in hospitalization costs between races in patients with TC-CS.
Abstract 17450: Sex Influences the Gut-Lung Microbiome Composition in Schistosomiasis-Associated Pulmonary Arterial Hypertension
Authors: MarinhoFerreirados Santos Ygor , Loya Omar , Sun Jun , Oliveira Suellen Darc D
Published: December 2023

Introduction:
Pulmonary arterial hypertension (PAH) is an uncurable cardiopulmonary disease highly incident in women. Infection by the intravascular parasite Schistosoma mansoni recapitulates several aspects of widespread inflammation that leads to PAH (Sch-PAH). Our data indicate that after infection, the S. mansoni eggs translocate within the cardiopulmonary system, disturbing gut-lung microbiome and leading to severe PAH. Hypotheses: S. mansoni eggs disturb the lung microbiome, contributing to vascular inflammation and PAH in a sex-dependent manner.

Methods:
To test this hypothesis, we induced Sch-PAH in end-Scl.creERT2;Rosamt/mg mice by intraperitoneal sensibilization with 240 eggs/gram body weight (bw; 2 weeks) followed by intravenous injection of 175 eggs/gram bw. After 7 days, we analyzed the Right Ventricular Systolic Pressure and hypertrophy (RVSP; RVH). Lung sections were used for TUNEL stain and for microbiome analysis by shotgun metagenomics.

Results:
Metagenomic analysis revealed that S. mansoni egg infection disrupted the lung microbiome reducing α-diversity compared to controls. Infection also reduced the Phylum Ascomycota in the lungs, whereas the ratio Firmicutes:Bacteroidetes (F/B) remained similar between groups. No difference was observed in the Simpson and Chao index. In the guts, the infection did not alter the α-diversity or the relative abundance of Deferribacteres and Proteobacteria, but it significantly increased the ratio F/B, indicative of gut dysbiosis. In terms of sex, our preliminary data indicated female mice exhibit a lower lung α-diversity compared to male mice, characterized by a significant reduction in the Firmicutes Phylum (Mean reads: 0.013 and 0.119, respectively; reads normalized by Readcount with Children). Principal coordinate analysis identified a distance in the clustering pattern between sexes, which may account for microbiome differences in Sch-PAH. Finally, our data revealed increased RVH and presence of microvascular apoptosis in female compared to male group.

Conclusion:
Understanding whether the disrupted gut and lung microbiome composition contributes to the onset and progression of Sch-PAH in a sex-dependent manner opens a novel therapeutic direction.
Abstract 17453: In vitro Aspirin Responsiveness Can Predict Platelet Hyperreactivity and Cardiovascular Risk
Authors: Liberow Sarah , Luttrell-Williams Elliot , Xia Yuhe , McGirl Siobhan , Kennedy Lauren , Fadzan Maja , Akinlonu Adedoyin , Barrett Tessa A , Berger Jeffrey S
Published: December 2023

Background:
While antiplatelet therapy decreases cardiovascular events, insufficient platelet aggregation suppression by antiplatelet therapy is associated with an increased risk of cardiovascular events. In this study, we developed a diagnostic tool to establish an individual’s “aspirin (ASA) responsiveness”
in vitro
and investigated its association with other metrics of platelet activity and cardiovascular risk.

Methods:
In 115 subjects off all antiplatelet therapy, platelet aggregation in response to high-dose of arachidonic acid (AA; 1.5 mM) with and without incubation of platelet-rich plasma with ASA (3 mM) was measured by light transmission aggregometry (LTA). ASA responsiveness was defined as ([% aggregation to AA - % aggregation to AA + ASA] / % aggregation to AA) x 100. Next, we correlated ASA responsiveness with other metrics of platelet activity. Finally, we evaluated its clinical significance in a cohort of patients undergoing lower extremity revascularization (LER) followed longitudinally for cardiovascular events.

Results:
Among 115 participants (mean age 50.3 years old, 65% female, and 43.5% underrepresented minorities, off all antiplatelet therapy), mean % aggregation to high-dose AA was 89.5% ± 3.5. In vitro ASA responsiveness was variable, mean 73.72% ± 15 (range: 13.7% to 97.6%). ASA responsiveness was lower in older (P<0.05) and female participants (P<0.05) and was not associated with race/ethnicity, diabetes, or platelet count. Lower ASA responsiveness was associated with a significant increase in platelet aggregation to epinephrine (0.4 μM, P=0.0004), ADP (1.0 μM, P=8.89x10
-9
), and collagen (0.2 μg/mL, P=1.16x10
-9
). In an independent cohort of 67 patients undergoing LER, lower
in vitro
ASA responsiveness (e.g. a reduced platelet-inhibiting effect), was associated with a significantly increased risk of major adverse cardiac and limb events (1
st
tertile-63.6%, 2
nd
tertile-50.0% and 3
rd
tertile-27.3%; P=0.016 for trend).

Conclusions:
Reduced ASA responsiveness is associated with increased platelet activity and a higher risk of cardiovascular events. We propose that this rapid, relatively simple assay may be used preclinically for ASA testing and to identify individuals at high cardiovascular risk.
Abstract 17464: Peripheral Immune Cell Inflammatory Activation and Metabolic Dysregulation in Single Ventricle Congenital Heart Disease
Authors: Sanchez Erin E , Zegelbone Phillip , Pietra Ashley E , Turner Mary E , Li Brett A , Nakano Stephanie J , Garcia Anastacia
Published: December 2023

Introduction:
While heart failure (HF) is a leading cause of death and indication for transplant in single ventricle (SV) patients, the molecular mechanisms underlying HF progression are poorly understood. Chronic inflammation can initiate and accelerate pathological outcomes in patients with virtually every form of cardiovascular disease, yet our understanding of the impacts of immunologic alterations in SV are inadequate. Here, we test the hypothesis that peripheral immune cells (PBMCs) from SV patients display a pro-inflammatory and metabolically dysfunctional phenotype that contributes to progressive cardiac dysfunction.

Methods:
Pediatric SV patients were categorized based on ventricular function, including those with reduced systolic function (SVHF, n=32), Fontan failure (Fontan Failure, n=7), or healthy control (healthy control, n=18). PBMCs were isolated from whole blood by density gradient centrifugation. To assess the impact of the PBMC extracellular milieu, we treated isolated cardiomyocytes with human plasma. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer (Agilent). Statistical analysis was performed using a Kruskal-Wallis and post-hoc Dunn’s multiple comparisons test. Total RNA sequencing was performed to identify dysregulated pathways.

Results:
PBMCs from SVHF patients display decreased metabolic function (OCR, A) and increased glycolysis (ECAR, B). PBMCs from SVHF patients also display significant alterations in immune, inflammatory, and metabolic pathways (C). Moreover, plasma from SVHF patients decreases cardiomyocyte energetics.

Conclusions:
These data suggest that immune cells from SV patients display a pro-inflammatory and metabolically dysfunctional phenotype, with an increased dependence on glycolysis. Therefore, our data highlight a role for SV PBMCs to potentiate progressive cardiac dysfunction in this population and provide a novel avenue for therapeutic intervention.
Abstract 17465: Analysis of Intra-Operative Heart Rates Reveals a Novel Sub-Phenotype in Coronary Artery Bypass Grafting Patients
Authors: Abbas Mostafa , Morland Thomas , Kirchner H Lester , Hall Eric S , Shuhaiber Jeffrey , El-Manzalawy Yasser
Published: December 2023

Background:
We aim to investigate the use of intra-operative heart rate (HR) trajectories to develop and characterize sub-phenotypes of coronary artery bypass grafting (CABG) patients with distinct risk and outcome profiles.

Methods:
We used a retrospective cohort including 4194 CABG patients admitted to a large rural healthcare system between 2012 and 2021. Functional data analysis (FDA) was applied to patients’ intra-operative HR trajectories to identify distinct sub-phenotypes.

Results:
The elbow method suggested that the optimal number of clusters is four. Fig. 1 shows the mean HR trajectory curve (top) and Kaplan-Meier survival curve (bottom) for each of the four identified groups. G1 (Low HR) includes 35.2% of the patients with median age 68 years. Patients in G1 had the lowest ICU after CABG length of stay (LoS) of 76.1 hours and the longest CABG median procedure duration of 4.6 hours. Assignment to G1 was significantly associated with shorter ICU LoS (p= 2.2E-6). G2 (Intermediate HR) includes 35.4% of the patients with median age of 67 years. Patients in G2 had the highest prevalence of urgent admissions, 25.5%. Assignment to G2 was significantly associated with shorter ICU LoS (p=0.016). G3 (Increasing HR) includes 15.6% of the patients with median age 67. Patients in G3 had the shortest median procedure duration of 3.68 hours. Those patients were found to be significantly at risk of prolonged ICU stays (p=0.0002). Finally, G4 (High HR) includes 16.2% with the lowest observed median age of 65 years. Patients in G4 have the highest prevalence of in-hospital mortality (5.2%), 30-day readmission (4.3%), and 1-year mortality (4.8%). Assignment to G4 was significantly associated with the following outcomes: prolonged ICU stays (p=2.62e-9); in-hospital mortality (p=8.03e-5); 30-day readmission (p=0.017); and 1-year mortality (p=0.02).

Conclusions:
CABG sub-phenotypes based on intra-operative HR trajectories had distinct clinical characteristics and outcomes.
Abstract 17493: Racial/Ethnic Under-Representation in Early Phase Clinical Trials
Authors: White Halima , Idris Muhammed , Onwuanyi Anekwe , Palaniappan Latha , Lewis Eldrin F , Pemu Priscilla , Clark Kira , Ritter Victor , Shen Sa , Qin FeiFei , Igwe Joseph-Kelvin , Cruz Erin R , Johnson Cati Brown , Cross Jo Ann , Stefanick Marcia L , Wang Paul J
Published: December 2023

Introduction:
There is severe underrepresentation of racial and ethnic groups in many cardiovascular clinical trials. Early-phase clinical trials examine the action and safety limits of treatment and thus, underrepresentation may have particularly deleterious effects.

Hypothesis:
Ethnic and Racial groups are underrepresented in early-phase trials.

Methods:
Using the clinicaltrials.gov database, we examined the racial and ethnic representation in Phases 1, 2, 3, and 4 in completed heart failure clinical trials (N=89) with reported results from 2016-2021. We examined the proportion of trials with a representation equal or greater than % U.S. Census population (12% for African American (AA), 19% for Hispanic/Latino (HL), and 7% for Asian (AN)) and determined the median trial representation percentage for AA, HL, and AN groups. Using Chi-square analysis we compared the percent representation across the trial phases.

Results:
We found that 49%, 91%, and 87% Phase 1 and 2 trials have a lower AA, HL, and AN representation, respectively, compared to that in the U.S. Population (Table 1). HL and AN representation in Phase 1 and 2 trials is particularly low. There is significant variation in AA, HL, and AN representation across all trial phases(p<0.001).

Conclusions:
Significant underrepresentation of racial and ethnic groups persist in contemporary Phase 1 and 2 trials. Efforts to create a standard for collecting and reporting demographics along with increasing racial and ethnic group representation closer to US population may reduce the risk of future adverse events.
Abstract 17521: Esmolol-Associated Skin Necrosis: An Uncommon Adverse Reaction
Authors: Nnadi Ekendilichukwu , Khatun Nazima , Leon Scherly , Graham-Hill Suzette
Published: December 2023

Background:
We report a case of a patient admitted to the cardiac care unit for evaluation of a non-ST-elevation myocardial infarction (NSTEMI) in the setting of atrial flutter (2:1) who developed a bullae and skin necrosis secondary to esmolol infusion.

Case presentation:
A 48-year-old male with a past medical history of hypertension presented with exertional chest pain with associated shortness of breath and palpitations and was being evaluated for NSTEMI. Vitals were significant for blood pressure of 191/115 and heart rate of 125. Labs were significant for troponin I of 33.16 (<=0.15 ng/mL), which peaked at 38.24, and creatinine of 2.5. Electrocardiogram demonstrated atrial flutter 2:1 conduction with a rapid ventricular response. While in the cardiac critical unit, he was placed on an esmolol drip for rate control. Twenty-four hours after administration of the esmolol through a peripheral intravenous line (PIV), the patient began to feel pain with moderate edema around the site of the injection. The PIV was removed, and cold compresses were applied. Approximately 5-7 hours later, the patient developed multiple ring-like bullae around the injection site. Physical examination was noted for cold and tenderness to palpation with paresthesias. General surgery was consulted for compartment syndrome, which was ruled out. The cutaneous changes progressively worsened through admission, persisting in size and appearance with rupture and ulceration, and necrosis one week later (see image 1).

Conclusion:
Although rare, esmolol can lead to skin necrosis and early identification is necessary for appropriate intervention including cessation of the culprit agent.