bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11797: Totum-854 Anti-Oxidative Effect is Associated With Reduction of Blood Pressure and Tissue Remodeling in Spontaneous Hypertensive Rats
Authors: Ripoche Doriane , Michaux Arnaud , Pialoux Vincent , Vallier Marie , Langhi Cedric , Chavanelle Vivien , Le Joubioux Florian , MAUGARD Thierry , Otero Yolanda F , PELTIER Sébastien , Sirvent Pascal
Published: June 2023

Introduction:
Arterial Hypertension (AHT) is a major cause of premature death worldwide. Totum-854 (T-854) is a polyphenol-rich botanical composition dedicated to reduce the risk of developing AHT. We assessed its chronic effects on blood pressure in spontaneous hypertensive rats (SHR) and studied mechanisms of action involved.

Methods:
SHR rats received vehicle or T-854 (1000mg/kg) per os once a day for 8 weeks. Arterial pressure was recorded once a week with a radio-telemetry device (HD-S10, DSI). At the end of supplementation, rats were euthanized, and tissues were sampled out to analyze oxidative stress enzyme activities and gene expression profile. Media thickness was measured on aorta, embedded in paraffin and stained with Masson’s trichrome. w
1118
male drosophila were fed a diet containing paraquat (5mM) supplemented or not with 0,45% T-854. Mortality was recorded once a day.

Results:
In T-854-supplemented SHR rats, changes in SBP and DBP were significantly different in comparison to vehicle group (p<0.05), with both parameters being maintained below vehicle values from the 2
nd
week of supplementation to the end of the study. After 8 weeks of supplementation, antioxidant enzymes of supplemented rats exhibited increased SOD and catalase activity in plasma and myocardium, respectively. Moreover, the analysis of the expression of genes associated with oxidative stress showed a significant decrease in aortic Cybb and a significant increase in cardiac Sod1. T-854 antioxidant effects were associated with aorta and cardiac tissue remodeling, with an increase in aortic Col4a5 gene expression as well as a decrease in media thickness by 10% in supplemented rats and a decrease in cardiac MMP-2 gene expression. Finally, the antioxidant effects of T-854 in rats were confirmed in paraquat-fed drosophila, with a significant improvement of survival (p<0.0001) and a median survival increased by 58% in comparison to paraquat diet alone.

Conclusion:
Chronic T-854 supplementation prevents AHT development in SHR rats. Remodeling of aortic and cardiac tissues is associated with an antioxidant effect that was confirmed in paraquat-fed drosophila. Taken together, T-854 appears as an efficient strategy to prevent AHT.
Abstract 11803: Applicability of the New Proposed Criteria for Iron Deficiency in Japanese Patients With Heart Failure
Authors: Tada Atsushi , Nagai Toshiyuki , Koya Taro , Nakao Motoki , Ishizaka Suguru , Mizuguchi Yoshifumi , Aoyagi Hiroyuki , Imagawa Shogo , Tokuda Yusuke , Takahashi Masashige , Kato Yoshiya , Machida Masaharu , Matsutani Kenichi , Saito Takahiko , Anzai Toshihisa
Published: June 2023

Backgrounds:
Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF). A recent study from a large single-center chronic HF cohort including predominantly white British population showed that ID defined by current guideline criteria was not associated with poor outcome, and a new ID criteria targeting for HF population was proposed. However, its external applicability is unclear.

Methods:
We prospectively examined consecutive 711 chronic HF patients and measured serum iron, transferrin saturation (TSAT) and serum ferritin from a Japanese multicenter registry. The proposed ID criteria were TSAT <20% and serum iron ≤13 mmol/L and the guideline ID criteria were serum ferritin <100 ng/mL or, when ferritin was 100-299 ng/mL, TSAT <20%. The primary outcome was all-cause death.

Results:
Of studied patients (433 male, mean age 71 ± 13 years, mean left ventricular ejection fraction 47 ± 16%), 198 (28%) and 416 (59%) met the proposed and guideline ID criteria, respectively. During a median follow-up period of 441 (IQR 306-564) days, the primary outcome occurred in 50 patients. There was no significant difference on primary outcome between the patients with and without guideline ID criteria (
P
= 0.24) (
Figure A
), while patients with serum iron ≤10 mmol/L showed a higher mortality than those without (
P
= 0.004) (
Figure B
). In multivariable Cox regressions, the proposed ID criteria, but not guideline ID criteria, were independently associated with higher mortality (HR 1.92, 95% CI 1.06-3.47; and HR 1.42; 95% CI 0.79-1.24, respectively) adjusted for significant covariates including age, hemoglobin, estimated glomerular filtration rate and log NT-proBNP, and the Meta-Analysis Global Group in Chronic Heart Failure risk score.

Conclusions:
As defined by the proposed criteria, but not the guideline criteria, ID was associated with higher mortality in patients with chronic HF, suggesting that the proposed ID criteria might be applicable to Japanese population.
Abstract 11804: Improved Recovery Times and Postoperative Outcomes After Cardiac Surgery Done Under Thoracic Epidural Anaesthesia: A Systematic Review, Meta-Analysis, With Trial Sequential Analysis
Authors: Chiew John K , Low Christopher J , Zeng Kieran , Goh Zhi Jie , Ling Ryan R , Chen Ying , Ti Lian Kah , Ramanathan Kollengode
Published: June 2023

Background:
Research on fast-track recovery protocols postulate epidural anaesthesia (TEA) in cardiac surgery contribute to improved postoperative outcomes. However, concerns about TEA’s safety and current equivocal evidence, hinder its widespread usage. We conducted a systematic review and meta-analysis to assess the effects of TEA in cardiac surgery.

Methods:
We searched four databases for randomised controlled trials (RCTs) assessing the use of TEA against only GA in adults undergoing cardiac surgery, up till 4 June 2022. We conducted random effects meta-analyses (DerSimonian and Laird), evaluated risk of bias using the Cochrane Risk-of-Bias 2 tool, and rated certainty of evidence via the GRADE approach. Primary outcomes were ICU and Hospital length of stay, with other outcomes including postoperative complications. Trial sequential analysis (TSA) was conducted on all outcomes to elicit statistical and clinical benefit.

Results:
Our meta-analysis included 39 RCTs (1941 TEA patients, 2047 GA patients). TEA significantly reduced ICU LOS (Figure 1: -6.8 hours, 95%-CI: -10.8 to -2.8, p=0.0009), hospital LOS (-0.7 days, 95%-CI: -1.2 to -0.2, p=0.0051), and extubation time (-2.8 hours, 95%-CI: -3.8 to -1.8, p=0.0001). However, there was no significant reduction in mortality. TSA found that the cumulative Z-curve passed the TSA-adjusted boundary for ICU LOS (see below), hospital LOS, and ET, suggesting a clinical benefit. TEA also significantly reduced transfusion requirements, pain scores, delirium, arrhythmia, and pooled pulmonary complications, without additional complications such as epidural hematomas.

Conclusions:
TEA reduces ICU and hospital lengths of stay, and postoperative complications in patients undergoing cardiac surgery with minimal reported complications. These findings favour the use of TEA in cardiac surgery, and warrants consideration for use in cardiac surgeries worldwide.
Abstract 11812: Effects of Statins on Epicardial Adipose Tissue in Coronary Artery Disease
Authors: Raffiee Nur Amirah Syahindah , Yap Hsin Tung , Loong Yan Ting , Elankovan Arun , Wang Xiaomeng , Leng Shuang , Ng Jaryl Chen Koon , Huang Weimin , Lee Hwee Kuan , Chan Mark , Teo Lynette , Yew Min Sen , Tan Swee Yaw , Zhong Liang , Baskaran Lohendran
Published: June 2023

Introduction:
Coronary artery disease (CAD) is linked to many modifiable cardiovascular risk factors (CVRF) like smoking, diabetes, hypertension, hyperlipidaemia and obesity. High Epicardial Adipose Tissue (EAT) Hounsfield Unit (HU) attenuation using Non-contrast Computed Tomography (NCCT) is associated with more inflammation. Statin is believed to stabilise coronary plaque and reduce inflammation. However, its effects on EAT volume (EATv) and EAT HU is unknown. In this study, we quantified EAT and compared total EATv, mean EAT HU and percentage of EATv within -60 to -30 HU and -70 to -30 HU between group with statin treatment (S) and group with no statin (NS) treatment in an Asian cohort.

Methods:
343 patients presenting with stable chest pain and no previous known CAD were recruited. Pericardium was segmented from NCCT. EAT volume (in cm3) and mean attenuation (in HU) were quantified with -190 to -30 HU threshold within pericardium. In subanalysis, percentage of EAT volume in the HU limits of -60 to -30 and of -70 to -30 were calculated. EAT parameters were compared between S group and NS group, adjusting for hypertension, hyperlipidemia, diabetes and smoking history.

Results:
The cohort comprised 343 patients (M:F 65%:35%; mean age 59±10 years old), with prevalence of hypertension (54%), hyperlipidemia (74%) and diabetes (21%), and smoking (14%). Median coronary artery calcium score was 96.0 (21.0-324.0). Mean EAT HU was significantly lower in S than NS group (p=0.024). Percentage of total EAT within the -60 to -30 HU range was also significantly lower among S than NS (p = 0.026). This was also observed using -70 to -30 HU range (p = 0.025). EATv was not significantly different between S and NS groups (p = 0.159).

Conclusions:
Patients on statin treatment showed lower EAT attenuation, with lower EAT HU and percentage of EAT volume within the HU ranges of -60 to -30 and -70 to -30. This suggests that statin use is associated with reduced EAT inflammation independent of EAT volume.
Abstract 11827: A Case of Rapidly Progressive Aortic Valve Stenosis Secondary to Chronic Hypercalcemia
Authors: Gozun Maan Kathryn L , Ali Mohammed , Nagamine Todd , Nath Limpruttidham , Alan Kuo
Published: June 2023

Introduction:
Moderate hypercalcemia may be well-tolerated, but rapid calcium deposition to the aortic valve may have life-threatening consequences.

Clinical case:
We present a case of a 77-year-old female with a history of retroperitoneal liposarcoma complicated by hypercalcemia. The patient had had recurrent hypercalcemia for the past 6 months, ranging from 12-14 mg/dL. She complained of 4 weeks of progressive dyspnea and orthopnea. Physical exam showed jugular venous distension and bilateral pitting edema. A transthoracic echocardiogram (TTE) showed critical aortic stenosis (AS) with a valve area of 0.4 cm2, peak velocity of 6 m/s, and a mean gradient of 90 mmHg (Figure 1). Her last TTE just 9 months prior showed mildly thickened aortic valve leaflets without evidence of stenosis with a valve area of 2.2 cm2, peak velocity of 1.4 m/s, and mean gradient of 4 mmHg (Figure 2).

Discussion:
The most common cause of AS is age-related calcification. However, the role of hypercalcemia in AS has not been well-defined. Typically, the valve area is expected to decline by 0.1cm2 per year. Surprisingly, our patient’s valve area decreased from 2.2 cm2 to 0.4 cm2 in just 9 months. Rapid decline is usually associated with typical cardiovascular risk factors, however, studies have begun to recognize hypercalcemia as a potential risk factor for rapid progression. In our case, we believe our patient suffered from rapidly progressive AS secondary to chronic hypercalcemia due to malignancy.

Conclusions:
The severity of AS should be closely monitored in hypercalcemia and further studies are warranted to develop strategies for secondary prevention.
Abstract 11836: Lack of Engagement in Physical Activity Predicts All-Cause of Mortality and Rehospitalization in Patients With Heart Failure
Authors: Cha Geunyeong , Chung Misook L , Lennie Terry A , Lin Chin-Yen , Biddle Martha J , Wu Jiarong R , Moser Debra K
Published: June 2023

Background:
Lack of physical activity is associated with a higher risk of mortality and rehospitalization for patients with heart failure (HF). Although exercise is recommended to patients with HF to optimize health, engagement in physical activity (EPA) remains poor due to many barriers. There is limited knowledge about whether EPA is a unique predictor of event-free survival.

Purpose:
The purpose of this study was to determine whether EPA was an independent predictor of event-free survival in patients with HF controlling for demographic, clinical factors, and depressive symptoms.

Method:
We included 1135 patients with HF who completed a survey of EPA (Medical Outcomes Study Specific Adherence Scale [MOS-SAS]), depressive symptoms (Patient Health Questionnaire-9), and demographic and clinical characteristics (age, sex, smoking status, body mass index, and NYHA class). They were followed for 2-years. Event-free survival was the composite endpoint of time to all-cause hospitalization or death. Patients were categorized into EPA (stated engaged in physical activity at least once a week) and non-EPA (stated did not engage in physical activity at all) groups using an activity item of the MOS-SAS. Cox regression analysis was used to determine if EPA was an independent predictor of event-free survival.

Result:
Among patients (mean age = 64 ± 12.7 years, 64% male, 83% white, 44% NYHA class III/IV), 65% engaged in physical activity, while 35% did not. During follow-up, 118 deaths and 385 rehospitalizations occurred. Patients in the non-EPA group were 1.3 times more likely to die or be hospitalized compared with patients in the EPA group (HR =1.255, 95% CI: 1.039 - 1.517).

Conclusion:
We found that EPA, even at a low level (at least once a week) was beneficial in reducing the risk of mortality and hospitalization events. Innovative interventions should be developed to motivate non-EPA patients to engage in physical activity.
Abstract 11858: ATIC-Mediated De Novo Purine Synthesis Protects Endothelial Cells From Disturbed Flow-Induced Injury in Atherosclerosis
Authors: Ma Qian , Yang Qiuhua , Varadarajan Sudhahar , Fukai Tohru , Fulton David , Huo Yuqing
Published: June 2023

Aims:
Disturbed flow at arterial bifurcations and curvatures of blood vessels, combining with other atherosclerotic risk factors, promotes endothelial cell (EC) DNA damage and the subsequent EC death, compromises the integrity of the endothelial barrier and ultimately leads to the formation of atherosclerotic lesions. ECs reprogram their metabolism to protect them from atherogenic injury induced by disturbed flow.
De novo
purine synthesis (DNPS) has been reported to regulate DNA repair and cell proliferation in cancer cells, however, its role in atherosclerosis has not been determined. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) is the enzyme that catalyzes last two steps of DNPS. We investigated the role of ATIC-driven DNPS in flow-induced EC metabolic reprogramming and in the development of atherosclerosis.

Methods and Results:
The expression of DNPS and DNA damage associated genes in ECs exposed to disturbed flow were assessed by analyzing the published RNA-Seq datasets. ATIC protein expression and DNA damage were examined in the endothelium at atheroprone regions of mouse aortas. Mice with EC-specific
Atic
knockout were utilized to investigate the role of endothelial ATIC in atherosclerosis. ATIC-mediated DNPS were increased in ECs exposed to disturbed flow both
in vitro
and
in vivo
, which was highly associated with the increased DNA damage response. EC-specific
Atic
knockout enhanced DNA damage of ECs, EC apoptosis, EC permeability and the subsequent formation of atherosclerotic lesions.

Conclusion:
Enhanced ATIC-mediated DNPS in ECs exposed to disturbed flow supplies purine nucleotides to repair DNA damage and to preserve EC barrier integrity in vulnerable atheroprone regions, and ultimately protects against the development and progression of atherosclerosis.
Abstract 11886: Unique Insights of Pressure-Volume Loop Analysis During LVAD Ramp Study
Authors: Scheel Paul J , Cubero Salazar Ilton M , Kauffman Matthew , Weller Alexandra , Alkhunaizi Fatimah , Mukherjee Monica , Gilotra Nisha A , Sharma Kavita , Kilic Ahmet , Tedford Ryan J , Hsu Steven
Published: June 2023

Introduction:
Late right ventricular (RV) failure in left ventricular assist device (LVAD) patients leads to poor outcomes and mortality. Traditional hemodynamic assessment of RV function may lack sensitivity. Invasive pressure-volume loop assessment of RV function may prove more enlightening than currently available measures.

Methods:
Pressure-volume loop-derived RV end-systolic elastance (Ees) and effective arterial elastance (Ea)—indices of load-independent RV contractility and summated pulmonary arterial (PA) afterload respectively—were determined for control (n=14), PH (n=38), and LVAD (n=12) patients referred for right heart catheterization. LVAD patients were further dichotomized by referral reason: routine assessment vs. clinical heart failure (HF) (n=6 each).

Results:
At baseline, LVAD patients had lower RV Ees versus both PH (0.21 vs 0.41 mmHg/mL, p<0.001) and control (0.21 vs. 0.36 mmHg/mL, p=0.05) patients. Adjusting for age and afterload, RV-PA coupling, indexed by the ratio of Ees/Ea, was significant lower in LVAD vs matched non-LVAD patients (0.37 vs 0.65, p=0.01). Among LVAD patients, RV-PA coupling was significantly worse in those with clinical HF (0.26 vs 0.49, p=0.002), corresponding with depressed cardiac index (1.6 vs 2.3 L/min/m
2
, p=0.04) and a trend towards higher biventricular filling pressures. RV-PA coupling also responded differently with respect to speed change: while Ees/Ea improved with speed increase in well-compensated LVAD patients, it declined in those with HF (p=0.02 for interaction term, see Figure), driven by declining Ees.

Conclusion:
Intrinsic RV contractility is worse in LVAD patients versus control and non-LVAD PH; this drives significantly worse RV-PA coupling in LVAD patients. In LVAD patients with HF, RV-PA coupling is significantly reduced and not necessarily improved by increases in speed.
Abstract 11905: Dexmedetomidine for Sedation During Epicardial Ablation for Ventricular Tachycardia: A Single-Center Experience
Authors: Conti Sergio , Sabatino Francesco , Sgarito Giuseppe
Published: June 2023

Introduction:
Epicardial ablation of ventricular tachycardia (VT) is mainly performed under general anesthesia (GA). However, GA lowers blood pressure, may interfere with arrhythmia induction, and the use of muscle relaxants precludes identification of the phrenic nerve. Moreover, an anesthesiologist's is required during GA for the whole procedure, which may not always be possible.

Hypothesis:
The aim of there study was to evaluate the feasibility and safety of epicardial VT ablations under conscious sedation using dexmedetomidine.

Methods:
Between 2018 and 2022, all patients who underwent epicardial VT ablation under dexmedetomidine infusion were prospectively enrolled. All patients received premedication with paracetamol 1 g (acetaminophen 10 mg/ml) and ketorolac 30 mg. Sedation protocol included an i.v. bolus of midazolam (0.03-0.05 mg/kg) followed by continuous infusion of dexmedetomidine (0.2-0.7 mcg/kg/h). In addition, an i.v. fentanyl bolus (0.7-1.4 mcg/kg) was given for short-term analgesia, followed by a second dose after 30-45 minutes. Sedation-related complications were: hypoxia (S02<90%), severe hypotension (MAP<60 mmHg), and bradycardia (HR <45 b/m).

Results:
Seventy-one patients with drug-refractory recurrent VT underwent epicardial or endo-epi ablation under conscious sedation. Standard percutaneous sub-xiphoid access was attempted in all patients. in 2 patients the procedure was switched to GA because of intractable pain during epicardial catheter's manipulation. Data from 69 patients were analyzed. Mean age was 65.4±12.1 years and 66.6% of patients were males. Forty-seven patients (68.1%) had non-ischemic cardiomyopathy, 13 patients (18.9%) had ischemic-cardiomyopathy, and 9 patients (13%) had myocarditis. Procedural-related complications occurred in five patients (7.2%), one transient phrenic nerve palsy, two pericarditis, and two vascular complications. No severe adverse events related to the sedation occurred.

Conclusions:
Prompt availability of anesthesia support remains crucial for epicardial VT ablation. Continuous infusion of dexmedetomidine in addition to midazolam and fentanyl seems to be a safe and effective sedation protocol in patients undergoing epicardial VT ablation.
Abstract 11913:
In vivo
Optical Coherence Tomography Angiography of the Coronary Microcirculation
Authors: Zhou Yirong , Kim Junyoung , Tearney Guillermo J , Aguirre Aaron D
Published: June 2023

Introduction:
Imaging the coronary microcirculation in the beating heart is challenging due to motion artifact from cardiac contraction and respiration, which limits the application of high-resolution microscopy techniques. In the brain and other tissues with less motion artifact, optical coherence tomography angiography (OCTA) has been successfully used in rodents to create label-free maps of blood flow down to the capillary level. We hypothesized that advanced cardiac and respiratory gating together with high-speed optical coherence tomography can be used to implement OCTA of the capillary microcirculation
in vivo
in the mouse heart.

Methods:
C57BL/6 mice (n=30) were imaged through a sternotomy while anesthetized and ventilated. OCTA was performed using a custom tissue stabilizer and a Thorlabs TEL 321 Spectral Domain OCT system, which was synchronized to physiologic signals using custom hardware and software and cardiac pacing protocols. The system had an optical center wavelength of 1300 nm and produced axial (depth) and lateral resolutions of 4.2 μm and 13 μm, respectively. Angiograms were created from the difference between two consecutive images acquired during diastole, and a volumetric three-dimensional scan was acquired over multiple cardiac cycles. Images were analyzed in MATLAB and ImageJ to produce projection angiograms of the coronary microcirculation.

Results:
OCTA with cardiac and respiratory gating can produce high-resolution angiograms of the coronary microcirculation without exogenous contrast agents. OCTA has improved imaging depth and field of view compared to conventional confocal microscopy, and can produce widefield coronary angiograms (Fig. 1A) while maintaining the ability to visualize individual capillaries (Fig. 1B).

Conclusion:
In vivo
OCTA can image the coronary microcirculation in the heart and will provide a powerful new tool for investigating coronary microvascular dysfunction in mouse models of heart disease.
Abstract 11929: Rare Presentation of Fetal Long QT Syndrome With 2:1 Atrioventricular Conduction
Authors: Woo Joyce , Cherny Sara , Chandler Stephanie , Brown Nicholas , Funk Hailey , Strasburger Janette F , Wakai Ronald , patel sheetal
Published: June 2023

Case Presentation:
A 34 year-old G2P1 mother with Long QT syndrome Type 2 (LQTS2), history of sympathetic denervation, implantable defibrillator, and strong family history of LQTS2 including sudden death, presented to fetal cardiology at 29+3 weeks gestation with fetal 2:1 atrioventricular (AV) conduction and a ventricular rate of ≈60 bpm on fetal echocardiogram without hydrops. Findings persisted at 30+5 weeks by echo. The patient’s KCNH2 p.Met645Ile variant was previously classified as a Variant of Uncertain Significance, but segregation analysis of the family by a genetic counselor upgraded the variant to Likely Pathogenic. Prior to pregnancy, the patient was taking nadolol, then started on 2000 IU of vitamin D at 30+6 weeks due to borderline vitamin D level. Within 24 hours of initiating vitamin D, fetal magnetocardiography (fMCG) demonstrated predominant sinus rhythm with 1:1 conduction at ≈120 bpm and occasional 2:1 AV conduction. The QTc measured ≈550 msec during 1:1 conduction, and ≈720 msec during 2:1 conduction.

Following the multidisciplinary diagnosis of fetal LQTS, several decisions were made. The patient declined amniocentesis, as the risk outweighed the benefit of additional genetic information. Daily home fetal heart monitoring, with goal heart rate 70-170 bpm, allowed for fewer fetal echos. Maternal vitamin D intake was liberalized to 4000 IU/day. Follow-up fMCG was recommended to exclude late-onset Torsade de Pointes, which would require transplacental treatment and complex perinatal management. Discussion with electrophysiology outlined longitudinal outcomes for the family, including potential need for neonatal pacing wires.

Discussion:
LQTS affects ~1/2,500 live births, with even fewer presenting with fetal AV conduction abnormalities. Optimized maternal vitamin D level may be associated with improved conduction. A multidisciplinary approach is crucial in diagnosis and management of these high-risk fetuses.
Abstract 11945: Improved Outcomes in Severe Primary Graft Dysfunction Following Heart Transplantation With Donation After Circulatory Death Compared to Donation After Brain Death
Authors: Ayer Austin , Truby Lauren , Schroder Jacob , Casalinova Sarah , Green Cynthia , Bishawi Muath , Bryner Benjamin , Patel Chetan B , Devore Adam D
Published: June 2023

Introduction:
Primary graft dysfunction (PGD), the leading cause of early mortality after heart transplant, is more common following heart donation after circulatory death (DCD) than following donation after brain death (DBD). We conducted a single-center, retrospective cohort study to compare the incidence, severity, and outcomes of patients experiencing PGD after DCD compared to DBD heart transplant.

Methods:
We reviewed the medical records of all adult heart transplant recipients at our institution between March 2016 and December 2021. Patients undergoing multi-organ transplant were excluded. PGD was diagnosed within 24 hours after transplant according to modified ISHLT criteria and was classified by severity and ventricles involved.

Results:
A total of 459 qualifying patients underwent heart transplant during the study period, of whom 65 (14%) were DCD recipients and 394 (86%) were DBD recipients. The incidence of PGD in DCD and DBD recipients was 34% and 23%, respectively (p = 0.070). DCD recipients were more likely to experience severe, biventricular PGD than DBD recipients (19% vs. 7.3%, p = 0.004). Among patients with severe PGD, DCD recipients experienced shorter duration of mechanical circulatory support (ECMO, VAD, or balloon pump; mean 6.0 ± 2.5 vs. 12.1 ± 11.3 days, p = 0.039; Figure), shorter post-transplant hospital length of stay (32.4 ± 41.1 vs. 61.9 ± 47.7 days, p = 0.004), and a trend toward improved 60-day survival (100% vs. 80%, p = 0.170) and one-year survival (92% [95% CI: 76%-100%] vs. 69% [53%-84%]).

Conclusions:
DCD heart transplant recipients were more likely to experience severe, biventricular PGD than DBD recipients. Despite this, short- and medium-term outcomes among patients with severe PGD were improved in DCD compared to DBD recipients. These data suggest different mechanisms of graft dysfunction and recovery following DCD compared to DBD and support the expansion of the heart donor pool with DCD in most potential recipients.
Abstract 11946: Prioritization of Multiomic Rare Variants (RVs) Underlying Electrocardiogram (EKG) Traits Using Bayesian Hierarchical Modeling (“Watershed”)
Authors: Li Taibo , Ersaro Nicole , Strober Benjamin J , Arvanitis Marios , Duong ThuyVy , Brody Jennifer , Lin Henry J , Taylor Kent D , Rotter Jerome I , Rich Stephen S ,   NHLBI TOPMed Consortium, Sootedehnia Nona , Arking Dan E , Montgomery Stephen B , Battle Alexis
Published: June 2023

Introduction:
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >33 million people worldwide. EKG is a powerful tool to diagnose AF. Earlier studies found common and rare genetic variants associated with EKG traits and AF risk. However, each individual genome has thousands of RVs which have not been systematically characterized in EKG traits.

Hypothesis
Individuals with outlier levels of omic measurements in EKG relevant genes are enriched with functional RVs which contribute to AF risk.

Methods
We analyzed transcriptomic, methylomic, proteomic, and whole genome sequencing data from 1319 individuals in TOPMed Multi-Ethnic Study of Atherosclerosis. We prioritized RVs with Watershed integrating genomic annotations and omic outlier signals (Fig A). We applied Watershed posterior probabilities as weights for EKG trait association using 30 million RVs in 4559 individuals. We developed a polygenic risk score (PRS) using RV posteriors to assess risk stratification for PR interval.

Results
The multiomic Watershed model prioritized RVs with large effects as identified by PR interval GWAS (
Fig B
). Each signal contributed to distinct sets of variants. Watershed confirmed known EKG gene associations and implicated splicing outliers in
NDUFB8
as a novel association with QT interval. When incorporated in SKAT test, Watershed leveraged 10x more noncoding RVs and replicated associations between PR interval and
SCN5A
,
MYH6
,
NEBL
, and
GORASP1
(missed by the default SKAT model). An RV score synthesized across 494 genes was correlated with PR interval after adjusting for common variant PRS (
Fig C
), suggesting that Watershed-prioritized RVs can complement common variants to improve patient risk stratification.

Conclusions
Watershed is a promising framework to characterize RVs with functional effects, which informed trait-gene associations and improved patient risk stratification, enhancing mechanistic insights into EKG traits and AF diagnosis.
Abstract 11951: Acute Cardiac Contractility Modulation Assessment in Conventional 2D Monolayers and 3D Engineered Cardiac Tissues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Feaster TK , Feric Nicole , Pallotta Isabella , Narkar Akshay , Casicola Maura , Graziano Michael , Sobbi Rooz , Blinova Ksenia
Published: June 2023

Introduction:
Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical simulations are delivered to the myocardium during the absolute refractory period. We previously evaluated the effects of the standard CCM pulse parameters in isolated rabbit ventricular cardiomyocytes and 2D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers, on flexible substrate.

Hypothesis:
In the present study, we sought to extend these results to 3D microphysiological systems to develop a human-based model to evaluate various clinical CCM pulse parameters in vitro.

Methods:
HiPSC-CMs were studied in conventional 2D monolayer format, on stiff substrate (i.e., glass), and as 3D human engineered cardiac tissues (ECTs). Cardiac contractile properties were evaluated by video-based analysis and custom force analysis. CCM pulses were assessed at varying clinical ‘doses’ using a commercial pulse generator. Robust response was observed at physiological Ca concentrations [1.8 mM] for 3D ECTs.

Results:
Under standard acute CCM stimulation 3D ECTs displayed enhanced contractile properties including increased peak contraction amplitude (i.e., force), and faster contraction and relaxation kinetics. Moreover, 3D ECTs displayed enhanced contractility in a CCM pulse parameter dependent manner. The observed effects subsided when the acute CCM stimulation was stopped and gradually returned to baseline. Under comparable conditions, conventional 2D monolayer hiPSC-CMs, on stiff substrate, displayed neutral response.

Conclusions:
These data represent the first study of acute CCM stimulation in a 3D hiPSC-CM model and provides a preclinical model to assess various CCM signals in human cardiac tissues prior to in vivo animal studies.
Abstract 11952: Physician Preferences for Treatment of Low-Density Lipoprotein Cholesterol Among Patients With Atherosclerotic Cardiovascular Disease - A Discrete Choice Experiment
Authors: Graf Marlon , May Suepattra G , Chung Sukyung , Khera Amit , N'Dri Laetitia A , Cristino Joaquim , Electricwala Batul
Published: June 2023

Introduction:
Around 80% of patients with atherosclerotic cardiovascular disease (ASCVD) do not achieve adequate reduction of low-density lipoprotein cholesterol (LDL-C) in current clinical practice, especially among patients on statin monotherapy. Greater understanding of attributes favored by prescribing physicians may improve treatment outcomes.

Methods:
To understand attributes of putative statin ‘add-on’ LDL-C lowering therapies, we conducted a discrete choice experiment survey of 200 U.S. cardiologists and 50 primary care physicians (PCPs). The survey presented a series of discrete choices to respondents, systematically varied across 8 treatment attributes: % LDL-C reduction, myalgias, other side effects, route and frequency of administration, time to prior authorization, patient out-of-pocket cost (OOPC) and adherence. Data were analyzed using logistic regression with clustering and heterogeneity adjustments to estimate preference weights for each attribute.

Results:
Both cardiologists and PCPs most valued efficacy in LDL-C reduction, with odds ratio (OR) for treatment preference of 1.69 per additional 10% reduction in LDL-C, and minimization of monthly OOPC with OR of 0.90 per $10 increase. Cardiologists preferred injectable therapies, with 57.5% of respondents preferring a drug with attributes of a small interfering RNA (siRNA) injectable and 16.4% preferring attributes of a proprotein convertase subtilisin kexin type 9 inhibitor (PCSK9i) biologic over oral ezetimibe therapy, as compared to only 2.8% preference for siRNA injectable among PCPs vs. oral therapy. Across all respondents, preference for injectables was higher for patients with history of nonadherence, with 55.7% preferring a drug with health-care practitioner-based injection every 6 months and 25.4% preferring a drug with properties of monoclonal antibody-based home injections once or twice monthly.

Conclusions:
Results indicate LDL-C lowering efficacy is a primary driver of physician prescribing preferences, with PCPs placing increasing consideration on OOPC. For patients with suboptimal adherence - the majority of those seen in clinical practice - U.S. physicians are more likely to prefer less-frequent injectable to oral therapies.
Abstract 11967: Microrna-150 Overexpression Blunts Maladaptive Cardiac Remodeling in Mice With Cardiomyocyte-Specific Loss of β-Arrestin-Mediated β
1
-Adrenergic Receptor Signaling
Authors: Moukette Bruno , Kawaguchi Satoshi , Sepulveda Marisa , Kim Il-man
Published: June 2023

Background and Aims:
β-arrestins transduce alternative pathways independent of G protein signaling, a concept known as β-arrestin-biased signaling that is promoted by G protein-coupled receptor kinase (GRK) 5/6 phosphorylation on β-adrenergic receptors (βARs). The β
1
AR is found primarily in the heart (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β
1
AR signaling elicits cardioprotection by CM survival. We showed that a small noncoding RNA (ncRNA), microRNA-150 (miR-150) is upregulated by the β-blocker carvedilol acting through β-arrestin-mediated β
1
AR signaling, and that CM miR-150 confers cardioprotection (see Figure). Here, we investigate if miR-150 in part rescues maladaptive cardiac remodeling seen in mice with CM-specific abrogation of β-arrestin-mediated β
1
AR signaling.

Methods and Results:
Using CM-specific transgenic (TG) mice expressing a mutant β
1
AR (i.e. GRK
-
β
1
AR exhibiting impairment in β-arrestin-mediated β
1
AR signaling and miR-150 activation by carvedilol), we first develop a novel double TG (DTG) mouse line overexpressing miR-150 and CM-specific GRK
-
β
1
AR. We demonstrate that miR-150 improves maladaptive cardiac remodeling observed in CM-specific GRK
-
β
1
AR TG mice after chronic catecholamine stimulation. Genome-wide circular RNA, long ncRNA (lncRNA) and mRNA profiling analyses in DTG mouse hearts unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for miR-150’s beneficial effects. We further show that lncRNA Gm41664 and
Gdap1l1
have miR-150 binding sites, and that they are direct novel upstream and downstream regulators of miR-150. Lastly, protective roles of miR-150 in CMs are in part attributed to the functional repression of pro-apoptotic
Gdap1l1
and are mitigated by pro-apoptotic Gm41664 (see Figure).

Conclusions:
Our findings support that miR-150 contributes significantly to β
1
AR/β-arrestin-mediated cardioprotection by regulating a unique ncRNA and gene signature in CMs.
Abstract 11969: Effect of Aortic Valve Phenotype and Sex on Aortic Dilation: Results From the Progressa Study
Authors: Fleury Marie-Ange , Tastet Lionel , Shen Mylene , Capoulade Romain , Bernard Jeremy , Abdoun Kathia , Bédard Elisabeth , Arsenault Marie , Clavel Marie-Annick , Pibarot Philippe
Published: June 2023

Introduction:
Bicuspid aortic valve (BAV) is frequently associated with aortic valve stenosis (AS) and concomitant aortopathy. However, few studies have evaluated the effect of aortic valve (AV) phenotype on the risk of progressive dilation of aorta dimensions. The aim of this study was to compare the progression rate of aorta dimensions according to AV phenotype (i.e. BAV vs tricuspid aortic valve [TAV]) and sex in patients with AS.

Methods:
Three-hundred twenty AS patients (231 TAV and 89 BAV; mean age: 64±14 years, 72% men) recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Patients underwent Doppler-echocardiography annually to measure the AS hemodynamic severity and aorta dimensions including the aortic root (AR) at the sinus level and ascending aorta (AA) sections. The annualized change of echocardiographic parameters was assessed between baseline and last follow-up visit (median follow-up time: 4.01 [2.26 to 5.00] years).

Results:
Baseline AR diameters were similar between phenotypes and AA diameters were larger in BAV vs. TAV (34±5 vs. 34±4, p=0.43, 38±6 vs. 34±4, p<0.001, respectively). Median change in AR root diameter was similar in BAV vs. TAV (0.15 [-0.07 to 0.44] cm/year vs. 0.13 [-0.07 to 0.41] cm/year, p=0.69), whereas AA annualized change was larger in BAV (0.26 [0.02 to 0.52] cm/year vs. 0.14 [-0.06 to 0.40] cm/year, p=0.02). After multivariable adjustment, BAV phenotype was not a significant predictor of faster progression rate of AR or AA dilation (β: -0.003, p=0.98 and -0.095, p=0.25). In a separate analysis according to sex, the median changes in AR and AA were similar between women and men (p=0.53 and p=0.18). Predictors of AA progression rate in men were baseline AA diameter and AS severity (i.e. baseline peak aortic jet velocity) (all p≤0.03). In women, only higher low-density lipoprotein levels were significantly associated with faster AA progression (p=0.02). Regarding the AR annualized dilation, there were no significant predictors in both women and men (all p≥0.07).

Conclusion:
This study suggests that AV phenotype is not independently associated with faster dilation of the AR or AA in patients with established AS. However, the determinants of aorta dilation may be different between women and men.
Abstract 11983: Associations Between Circulating Proteins and Intracardiac Immune Populations in Immune Checkpoint Inhibitor-Associated Myocarditis
Authors: Zlotoff Daniel , Blum Steven , Ramesh Swetha , Kernin Isabela , Smith Neal , Sen Pritha , Zubiri Leyre , Tirard Alice , Nasrallah Mazen , Tantivit Jessica , Manakongtreecheep Kasidet , Arnold Benjamin , Chan PuiYee , Barth Jaimie , Juric Dejan , Sullivan Ryan , Boland Genevieve , Mino-Kenudson Mari , Stone James R , Thomas Molly F , Caplin Joshua , Reynolds Kerry , Neilan Tomas G , Villani Alexandra-Chloe
Published: June 2023

Introduction:
Myocarditis due to immune checkpoint inhibitors (ICIs), a type of cancer immunotherapy, is associated with high morbidity and mortality. The cellular and molecular pathogenesis of ICI myocarditis remains largely unknown. Identification of circulating factors associated with intracardiac pathology may aid new clinical approaches.

Hypothesis:
We hypothesized that ICI myocarditis is associated with increased abundance of intracardiac immune cells and upregulated inflammatory genes in the heart and serum.

Methods:
Heart tissue from 13 patients with ICI myocarditis was acquired by endomyocardial biopsy or autopsy; peripheral blood mononuclear cells (PBMCs) were also collected from ten of these patients and eight additional ICI myocarditis patients. Control heart tissue was derived from six hearts declined for transplantation (non-ICI-exposed) and from the biopsy and autopsy of one ICI-treated patient without myocarditis. The 10x Genomics Chromium system was used to generate single-cell RNA sequencing (scRNAseq) data from heart and PBMC specimens. Serum proteins were measured by core lab assay (for troponin T) or by multiplexed Luminex immunoassay.

Results:
Unbiased clustering of scRNAseq data from 77,071 cells recovered from heart samples revealed 37 cell subsets across 10 cell lineages. Myocarditis heart tissue demonstrated enrichment of T/NK cells (odds ratio 8.3, p=0.0006), B/plasma cells (OR 5.1, p=0.01), and dendritic cells (DCs) (OR 9.2, p=0.006) relative to controls. Circulating DC abundance was decreased in fatal (n=3) versus nonfatal (n=15) myocarditis cases (p=0.008), while intracardiac DC abundance was directly associated with serum troponin T values (p=0.02). The levels of five immunomodulatory factors - IL-15, CXCL9, CCL3, TNFα, and CCL21 - were found to be significantly upregulated transcriptionally in at least one intracardiac cell subset and at the protein level in the serum of myocarditis cases.

Conclusions:
Fatality status and troponin level associated with intracardiac DC abundance and multiple immunomodulatory genes were upregulated in both the heart and serum in ICI myocarditis. These observations may guide novel diagnostic and therapeutic strategies.
Abstract 11986: In-Hospital Outcomes in Patients With Peripheral Artery Disease Hospitalized for Acute Myocardial Infarction: From the NCDR Chest Pain Mi Registry
Authors: Faridi Kamil F , Li Shuang , Wang Tracy Y , Mena-Hurtado Carlos , Smolderen Kim G , Rymer Jennifer A , Curtis Jeptha P , Secemsky Eric A
Published: June 2023

Introduction:
Patients with peripheral artery disease (PAD) are at high risk for adverse cardiovascular events, including acute myocardial infarction (AMI). Though AMI care has improved, in-hospital outcomes for patients experiencing an AMI with comorbid PAD are not well described in recent practice. We hypothesized that patients with PAD would have higher rates of bleeding and mortality during AMI hospitalization.

Methods:
We assessed clinical characteristics and in-hospital major bleeding and mortality rates of patients admitted with AMI and comorbid PAD at 646 hospitals in the NCDR Chest Pain MI Registry from 1/2019 to 9/2021. Major bleeding and mortality were compared for patients with vs. without PAD using multivariable logistic regression.

Results:
Compared with patients admitted for AMI without PAD (n = 307,550), those with PAD (n = 24,585) were older, had more comorbidities including tobacco use, diabetes, prior AMI and heart failure, and more frequently presented with NSTEMI vs. STEMI. Patients with PAD had higher crude rates of in-hospital major bleeding (9.7% vs. 6.3%) and mortality (8.1% vs. 4.7%); in exploratory analyses, rates of other adverse in-hospital events were also higher (
Figure
). After multivariable adjustment, PAD was associated with an increased risk of major bleeding (adjusted OR [aOR] 1.23 [95% CI 1.17-1.30]). PAD was also associated with greater risk of in-hospital mortality (aOR 1.28 [95% CI 1.21-1.37]), particularly among patients over age 65 (aOR 1.32 [95% CI 1.23-1.42] for ≥65 years vs. 1.06 [95% CI 0.96-1.18] for patients <65 years; interaction p = 0.02).

Conclusions:
Among patients hospitalized with AMI, those with PAD have greater comorbidity burden and increased risk of major bleeding. Patients with PAD, particularly those who are ≥65 years, also have increased risk of in-hospital death. These findings highlight a need for improved preventive efforts, tailored care pathways, and greater focus on AMI management in PAD patients.
Abstract 11992: Novel Immune Profiling Utilizing Single-Cell Mass Cytometry in Pediatric Heart Failure
Authors: Patel Meghna D , Tsai Amy , Zhao Mingming , Hedou Julien , Luong Roger , Taylor Anne C , Bernstein Daniel , Gaudilliere Brice L
Published: June 2023

Introduction:
Pediatric end-stage heart failure (ESHF) is a diverse disease with significant morbidity. Many children are supported with ventricular assist devices (VAD), adding further high risk of complication. Specific markers for adverse events are unknown. Emerging evidence suggests the presence of inflammation and immune dysfunction in ESHF. Improved understanding of systemic immune dysfunction is a first step towards identifying biomarkers of ESHF. We hypothesize that the distribution and signaling of innate and adaptive immune cells differ in pediatric ESHF and healthy controls.

Methods:
A high-dimensional, single-cell mass cytometry immuno-assay was used to quantify 247 cell signaling events in whole blood from children with ESHF (n=18) and healthy controls (n=12). Cell signaling was assessed at baseline and after stimulation. Multivariate regularized regression modeling with Elastic Net (EN) was used to identify differences between groups (fig. 1A). Secondary analyses evaluated effect of ESHF+VAD (n=6). Statistical significance was established using Leave one out cross validation.

Results:
We identified an EN model that stratified ESHF vs. controls with high accuracy (fig. 1B). Model analysis revealed cell-type and signaling differences that spanned innate and adaptive immune components. ESHF showed depressed endogenous gdT cell frequency, pERK signaling in ncMCs, and elevated pSTAT3 and pSTAT4 in CD4+ T cells in response to cytokine stimulation. Additionally, the model predicted differences in ESHF vs. ESHF+VAD with high accuracy (fig. 1C-D).

Conclusions:
Comprehensive single-cell analysis identified a robust immune signature of pediatric ESHF that was further modulated by presence of a VAD. Individual features revealed novel innate and adaptive immune dysfunction. Future prospective studies will be key to identifying immunological biomarkers that facilitate clinical decisions and predict complications in pediatric ESHF.