bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17043: Role of Child Opportunity Index on Neonatal Mortality and 1-Year Mortality in Infant Congenital Heart Disease: A Contemporary Population-Based Report
Authors: Cota Phelan Paola , Steurer Martina , Costello John M , Santana Stephanie , Collins james , Branche Tonia , Sharma Meesha , Jelliffe-Pawlowski Laura , Peyvandi Shabnam
Published: December 2023

Introduction:
Although mortality has declined among infants with congenital heart disease (CHD), racial/ethnic and sociodemographic disparities persist. The child opportunity index (COI) is a census-based metric of neighborhood conditions based on education, health/environment, and social/economic domains. We sought to determine the impact of COI on neonatal and 1-year mortality of infants with CHD.

Hypothesis:
We hypothesized that neighborhood sociodemographic factors as measured by COI would have a greater impact on longer-term outcomes.

Methods:
This is a retrospective population-based cohort in California (2011-2017) of infants with CHD who underwent a cardiac intervention in the first year of life. COI was categorized into high, moderate, and low. Each COI domain was evaluated. The primary outcomes included 1-year mortality, neonatal mortality prior to 30 days of life, and days alive out of hospital in the first year of life (DAOOH). Uni- and multivariable logistic and linear regression were used.

Results:
The sample included 9,729 infants with an overall 1-year mortality rate of 8.2% and neonatal mortality rate of 3.5%. After adjusting for race/ethnicity, maternal age, sex, CHD severity (RACHS-1 category), birth weight z-score, and gestational age at birth, the odds of 1-year mortality were significantly higher among infants from low compared to high COI (1.37, 95%CI: 1.13, 1.67). In contrast, the adjusted odds of neonatal mortality were not different in low compared to high COI (1.20, 95%CI:0.89,1.61). Low and moderate COI groups had significantly lower DAOOH compared to high COI (low: -10.30, 95%CI: -15.2, -5.4; moderate: -7.43, 95%CI: -12.96, -1.89). Results were similar for each COI domain
(
Figure 1).

Conclusion:
Neighborhood factors reflecting the home environment influence outcomes beyond the neonatal period. Future studies are needed to determine whether targeting domains of the COI will mitigate ongoing risks of poor CHD outcomes.
Abstract 17044: Normal Ranges of Right Atrial Strain by Contemporary Echocardiography Software: A Prospective Comparative Cohort Study
Authors: Agrawal Ankit , El Dahdah Joseph , Arockiam Aro Daniela , Dong Tiffany , Majid Muhammad , Rodriguez L L , Grimm Richard A , Griffin Brian P , Popovic Zoran B , Wang Tom Kai Ming K
Published: December 2023

Introduction:
Right atrial strain (reservoir RASr, conduit RAScd and contractile RASct) are increasingly utilized in the clinical and research setting such as for diastology grading, heart failure and valvular heart disease. However, the feasibility and reference ranges of right atrial strain measurements by contemporary strain software on different vendor scanners are not well established. We evaluated and compared two-dimensional right atrial strain values, reference ranges and associated factors across three strain software vendors in healthy subjects.

Methods:
Healthy subjects (n=100) undergoing echocardiography during January-April 2023 were prospectively studied, with equal number by age-groups, gender and GE versus Philips scans. Right atrial strains were quantified using TomTec version 51.02 (Autostrain LA), EchoPAC version 206 (AFI-LA) and VVI software for statistical analyses.

Results:
The table shows the right atrial strain means (and lower limits of normal defined as 95
th
percentile) ± standard error by strain software, including RASr of 41.2±0.9% (29.6±1.6%) by TomTec, 35.9±0.7% (27.0±1.3%) by EchoPAC (which could only measure on GE scans), and 44.8±1.3% (27.6±2.2%) by VVI. EchoPAC measurements of right atrial strain were significantly less negative than TomTec or VVI (P<0.01), while TomTec has slightly less negative measurements than VVI for RASr only but similar for RAScd and RASct. Multivariable linear regression showed systolic blood pressure to be significantly associated with RASr measured by VVI with beta coefficient (95%CI) per 1 mmHg of 0.23 (0.08-0.38), why no factors were significantly associated with RASr measured by TomTec or EchoPAC.

Conclusions:
TomTec and VVI were vendor neutral for measuring right atrial strains, while EchoPAC can only measure this on GE scans. Normal means, lower limits of normal and associated factors of right atrial strain measurements by strain vendor were established for clinical applications.
Abstract 17047: Contribution of MDA-5/IL-10RA to Pulmonary Artery Homeostasis and Pulmonary Arterial Hypertension
Authors: Newcomb Geoffrey , Piper Bryce , Bogamuwa Srimathi , Goncharova Elena A , Farkas Laszlo
Published: December 2023

Introduction:
Pulmonary arterial hypertension (PAH) is a progressive and lethal disease. The current treatment options do not target pulmonary artery endothelial cell (PAEC) dysfunction. We have previously shown a role for the endosomal double stranded (ds) RNA receptor toll-like receptor 3 (TLR3) and its regulation via interleukin-10 (IL-10) in promoting PAEC dysfunction and experimental pulmonary hypertension (PH). Yet the role of the cytosolic dsRNA receptor melanoma differentiation factor 5 (MDA-5) in endothelial dysfunction is not known.

Hypothesis:
We hypothesized that a deficient MDA-5/IL-10 receptor A (IL-10RA) signaling axis expression exists in PAH PAECs as a potential cause of endothelial dysfunction.
Goals:
Our goal is to test the role of a potential new axis of MDA-5 and IL10RA in EC homeostasis and pulmonary hypertension.

Methods:
Western blot analysis of control and PAH PAECs and PA smooth muscle cells (SMCs) was conducted. Gene silencing was done using siRNA targeting MDA-5 and IL-10RA, followed by bulk RNA sequencing. Apoptosis was tested using Annexin V binding. IL-10 whole body knockout (IL-10
-/-
) and endothelial-specific IL-10RA haploinsufficient mice (IL-10RA
fl/wt
Cdh5-Cre
+
) and appropriate controls were exposed to chronic hypoxia and SU5416 (Hx/Su), followed by hemodynamics.

Results:
Our data show a reduction of MDA-5 in PAECs, but not in PASMCs. PAH PAECs further had reduced IL-10RA expression and application of dsRNA elevated IL-10RA expression in PAH PAECs. Knockdown of MDA-5 and IL-10RA caused differential expression of 2533 and 2638 genes, respectively. Comparative analysis revealed an overlap of differentially expressed genes (DEGs) in canonical pathways including reduced nitric oxide, VEGF, Apelin and Integrin signaling. Comparison also yielded overlapping DEGs for reduced cell survival, impaired cytoskeleton organization and migration. Gene silencing of MDA-5 resulted in increased PAEC apoptosis. IL-10
-/-
and IL-10RA
fl/wt
Cdh5-Cre
+
mice showed exaggerated PH.

Conclusions:
Our data indicate an impaired cytosolic dsRNA receptor MDA-5 and IL-10RA axis in PAH PAECs which contributes to endothelial dysfunction and PH. Experiments are underway to identify the detailed mechanisms underlying our findings.
Abstract 17055: Underweight and Obesity Among Asian Children at Age 3 to 5 Years: Implications for Counseling to Promote Cardiometabolic Health Across the Lifecourse
Authors: Bacong Adrian M , Greenspan Louise , Chandra Malini , Palaniappan Latha , Lo Joan C
Published: December 2023

Background:
Body mass index (BMI) is an important pediatric measurement that supports nutrition/weight counseling in children, especially for obesity. However, children with low BMI (<5
th
percentile or “underweight”) should be considered, as Asian children are at risk for adverse cardiometabolic health at lower BMI as adults.

Mehods:
Using electronic record data from well-child visits from 5361 Chinese, 6215 Filipino, 5775 South Asian, and 48,666 Non-Hispanic White (NHW) children with BMI at age 3 and 5 years in a US healthcare system, we examined BMI distribution, underweight (<5th percentile), obesity (≥95th percentile), and changes in BMI from age 3 to 5 years.

Results:
Underweight was higher in Asian vs NHW (highest for South Asian, 15.0%, age 3, p<0.01). Obesity was highest for Filipino (11.3%, age 5) and lowest for Chinese (3.6%) vs NHW (p<0.01). At age 3, trends in greater proportion with underweight vs obesity for Chinese (6.3% vs 3.0%) and South Asian (15.0% vs 6.5%) children were seen, but not Filipino (5.0% vs 9.7%) and NHW (4.0 vs 7.8%) children (Table), similar to age 5. Most children with underweight had height <25th percentile. By age 5, large proportions shifted out of underweight, with modest obesity increases (Table). Obesity transition was greatest for South Asian children.

Conclusions:
Among major Asian groups and NHW children, underweight was most prevalent in South Asian (1 in 7, age 3) and obesity most prevalent in Filipino (1 in 10, age 5) children. High obesity prevalence in Filipino children and greater BMI transition in South Asian children highlight ethnic differences in BMI that support targeted lifestyle counseling to improve future cardiometabolic health.
Abstract 17060: Preliminary Assessment of Artificial Intelligence Guided Echocardiographic Screening of Cardiac Amyloidosis
Authors: Stern Lily K , Marker Irene R , Duffy Grant , JOUNG SANDY , Kwan Alan C , Ebinger Joseph E , Rader Florian , Cheng Susan , Patel Jignesh K , Ouyang David
Published: December 2023

Background:
Cardiac amyloidosis (CA) diagnosis is often overlooked. Novel CA treatments underscore the importance of early identification, as untreated CA has a poor prognosis. EchoNet-Screening is an echocardiogram-based artificial intelligence model to identify CA; previously refined by echocardiograms from patients with known CA. The goal of our study is to prospectively evaluate the accuracy of EchoNet-Screening across a large health system.

Methods:
All echocardiographic studies from our cardiac quaternary care center between 2019-2021 were batch-processed by EchoNet-Screening to produce a CA risk-prediction score (CA-RPS) for each patient based on the highest quality study, which is determined by the model. 336 patients with the highest CA-RPS underwent evaluation by detailed chart review by our CA clinical cardiology team. High risk patients without an alternative diagnosis are subsequently referred for CA specialty evaluation. (ClinicalTrial.gov/NCT05139797)

Results:
EchoNet-Screening was performed on echocardiographic images from 58,236 patients. Preliminary retrospective assessment of 336 patients with the highest CA-RPS revealed CA in 142 patients; almost half were not known from our advanced heart failure (AHF) registry and newly identified from chart review. 62 patients are pending prospective enrollment for CA subspecialty evaluation to further characterize the performance of EchoNet-Screening.

Conclusions:
Preliminary results from our trial demonstrate a high accuracy of EchoNet-Screening for detection of patients with known CA, emphasized by high rates of identification of CA patients even on initial chart review. Further work is ongoing to evaluate the performance of EchoNet-Screening to bring high-risk patients to new diagnoses and eventual care.
Abstract 17067: Long-Term Transplant-Free Survival is Improved in Hypoplastic Left Heart Syndrome With Cell-Based Therapy
Authors: Kaushal Sunjay , Naioti Eric , Ramdas Kevin N , Mehranfard Danial , McClain-Moss Lisa , Davis Michael E , Lambert Linda M , Menon Shaji C , Hibino Narutoshi , Morales David , Husain Adil , Masih Kaitlyn , Deatrick Kristopher B , Speed Sarah , Oliva Anthony , Hare Joshua M
Published: December 2023

Hypoplastic left heart syndrome (HLHS) is a univentricular congenital heart defect that has high morbidity and mortality and requires three-stage surgical reconstruction so that the right ventricle (RV) delivers systemic circulation. Poor outcomes result from RV failure in the systemic position. Accordingly, we conducted a phase I clinical trial (called ELPIS) of Lomecel-B™, an allogeneic bone-marrow derived cell-based therapy designed to improve cardiovascular performance, delivered as a one-time treatment during the Stage II (Glenn) surgery at approximately 4 months after birth. This trial met its primary endpoint (safety through 1-year post-treatment). To assess whether Lomecel-B™ has survival benefits, all ELPIS patients (
n=10,
7 males, and 3 females) were enrolled in a multi-year follow-on study and compared to a retrospective control group which was identified by a relevant clinical HLHS database. Patients in both studies were assessed for up to 5 years (range 3.5 - 5.0 years post-treatment for ELPIS) for mortality, heart transplants, and stage III (Fontan) surgery. Outcomes were compared with long-term historical data from patients in the Single Ventricle Reconstruction (SVR) Trial receiving the same shunt type at Stage I (Norwood) operation. 5-year Kaplan-Meier survival was 100% in ELPIS patients with none requiring heart transplant. This compared to 81.6% (95% CI= [76.5, 87.0]) transplant-free survival in the SVR trial through 5 years post-Glenn surgery, and a 5.2% (95% CI= [2.0, 8.3]) heart transplantation rate (Figure 1). No stem cell related safety issues were reported. These findings support Lomecel-B™ as a potential adjunct to HLHS reconstruction surgery to improve clinical benefits and reduce the need for subsequent heart transplantation. Further long-term follow-up and controlled trials are both warranted and underway.
Abstract 171: Hyperoxia Potentiates Pro-Inflammatory Immune Cell Activation in vitro
Authors: Rolland Tyler , Cucinotta Daniel , Zahra Sumbule , Weil Brian R
Published: December 2023

Objective:
Supplemental oxygen (O
2
) is commonly administered to critically ill patients to prevent hypoxemia, but there is growing evidence that hyperoxemia may be an equally deleterious physiological insult. Given the key role of immune activation in critical illness, we investigated whether oxygen tension influences the leukocyte response to pro-inflammatory stimuli
in vitro
.

Methods:
Naïve peripheral blood mononuclear cells (PBMCs) from healthy swine (n=12) were cultured at 10% O
2
(hyperoxia, n = 4), 5% O
2
(physoxia, n = 4), or 3% O
2
(hypoxia, n = 4) for 24 hours with and without lipopolysaccharide (LPS), mitochondrial DNA (mtDNA), or plasma collected from swine 1 hour following resuscitation from sudden cardiac arrest (post-SCA). Leukocyte activation was assessed via TNFα release (ELISA) and inflammatory surface marker expression (flow cytometry), and compared to basal media, transfection control, or pre-SCA plasma, respectively.

Results:
Hyperoxia significantly increased PBMC TNFα release in response to LPS, mtDNA, and post-SCA plasma compared to each respective control (
Figure).
In contrast, stimulated TNFα release was blunted (SCA plasma) or comparable (LPS and mtDNA) to that observed at physoxia. Consistent with these results, hyperoxia increased PBMC expression of inflammatory surface markers (CD163, CD172, CD14, and CD16) across all conditions, while less pronounced changes were evident after hypoxia.

Conclusions:
Hyperoxia potentiates TNFα release and shifts PBMCs towards an activated phenotype in the presence of several pro-inflammatory stimuli, including LPS, mtDNA, and plasma collected following resuscitation from SCA. These findings indicate that leukocyte activation is oxygen tension-dependent and suggest that hyperoxemia should be avoided in critically ill patients to minimize the risk of an excessive inflammatory response.
Abstract 17101: Impact of a Longitudinal Virtual-First Cardiology Program on Identification and Management of Complex Cardiovascular Disease
Authors: Perera Sudheesha , Goldberg Jana , Pratt Stacey , Abdullah Nicole , Mandrayar Lindsey , Littleton Sarah , McGregor Cheri , Wessler Jeff
Published: December 2023

Background:
In the face of rising healthcare expenditures nationally, current literature suggests that primary care-based longitudinal payment models may improve care quality and lower cardiovascular care costs. Despite innovation in this space, there has been no study that critically examines the efficacy of virtual-first cardiology care as an adjunct to existing primary care models.

Methods:
We performed a retrospective review of patients enrolled in Heartbeat Health’s Longitudinal Care program which provides virtual-first cardiology care to patients in partnership with their primary care team. The program included telemedicine visits with specialist cardiology teams, medication prescription, testing, and remote patient monitoring when indicated. We reviewed all new diagnoses, changes in blood pressure, initiation of guideline directed medical therapy (GDMT), and patient satisfaction.

Results:
The final cohort included 230 patients (average age = 71.7 yrs). Meaningful increases in new diagnoses were evident (Figure). Regarding blood pressure control, 30.8% saw improvement during the program and another 20.6% were at their goal by the time of graduation. Aspirin therapy (either primary or secondary prevention) increased from 28.3% to 35.7% in all-comers, while primary stroke prevention in patients with atrial fibrillation increased from 50% to 62.5%. Additionally, 46.5% (n=107) of patients were placed on GDMT for at least one of the conditions listed in Figure. Average patient Net Promoter Score was 87.

Conclusions:
Virtual-first cardiology care is a promising opportunity for value-based care organizations. Among other benefits, increased use of preventative therapy, enhanced GDMT, and newly found and managed diagnoses hold the potential to close gaps in care and reduce long-term costs.
Abstract 17102: Establishing Outcome-Based Severity Partitions for LV Dilation
Authors: Wallace Cecilia , Xu Yuanwei , Li Yangjie , Chen Yucheng , Han Yuchi
Published: December 2023

Background:
The 2015 American Society of Echocardiography chamber quantification guideline
1
included healthy population-based normal controls for left ventricular (LV) size, but not severity partitions due to the lack of data to support mild, moderate, and severe categories. In this study, we propose using adverse outcomes to define “severe” in non-ischemic dilated cardiomyopathy (DCM).

Methods:
778 adults with DCM were enrolled prospectively and underwent CMR from June 2012 to August 2020 at West China Hospital and followed for a median of 49 months
2
. 72 healthy Chinese adults served as controls. We evaluated “severe” increase in LV end-diastolic volume indexed to body surface area (EDVi), LVEDV/right ventricular (RV) EDV, and “severe” decrease in LV ejection fraction (EF) using receiver operator characteristic (ROC) and area under the curve (AUC) analysis based on cardiovascular outcome. We defined “moderate” as control mean +½ the standard deviation (SD) distance between control mean and “severe” and “mild” as between control mean +2 SD and “moderate”.

Results:
Of 778 participants, 190 experienced heart failure death, sudden cardiac death, or heart transplant. For LVEDVi, the “severe” dilation cut point was 184 mL/m
2
, 10.9 SD from control mean (71 ml/m
2
). Thus, “moderate” dilation starts at 128 ml/m
2
(control mean +5.4 SD) and “mild” starts at 92 ml/m
2
(control mean +2 SD). The LVEDV/RVEDV ratio partitions are similar to RVEDV/LVEDV partitions for pulmonary arterial hypertension
3
. It is well known that LVEDVi and LVEF have sex-based differences with females having smaller hearts and higher EF
4
. the volume ratio is slightly lower in females as compared to the males (Table 1).

Conclusion:
Severity of LV dilation and dysfunction based on LVEDVi, LVEF, and LVEDV/RVEDV can be determined by finding upper limits of normal, using outcomes to determine “severe” category, and using the SD distance between severe and control mean to determine mild and moderate categories.
Abstract 17125: Cardiovascular Mortality Defines Severe RV Enlargement in Pre-Capillary Pulmonary Hypertension by a RV to LV Volume Ratio >2.0
Authors: Raheel Mahad , Guo Jiajun , Chen Yucheng , Han Yuchi
Published: December 2023

Introduction:
Cardiac magnetic resonance imaging (CMR) is emerging as a non-invasive, prognostic tool in pulmonary arterial hypertension (PAH). The right ventricular (RV) end diastolic volume (EDV) to left ventricular (LV) EDV ratio measured by CMR is a parameter to evaluate RV size in relationship to the patient’s own LV and determine severity of dilation in patients with pulmonary arterial hypertension (PAH). An RVEDV/LVEDV greater than 2.3 has been proposed as a cutoff for severe RV enlargement in PAH based on mortality risk
1
. This study aims to confirm this cutoff in pre-capillary (pc) pulmonary hypertension (PH) patients using CMR and mortality data from two additional cohorts.

Materials and Methods:
In this retrospective study, we analyzed primary outcome cardiovascular mortality and CMR parameters in a database of patients from 2014 to 2021 with pcPH (mean pulmonary artery pressure > 20mmHg, PCWP<15 mmHg, WU≥ 3) determined by right heart catheterization (RHC) from Ohio State University (OSU) (n=42) and West China Hospital (WCH) (n=58). Patients with congenital heart disease, ischemic heart disease, valvular heart disease (moderate to severe AS, AR, MS, or MR), ECV <20 or >28, and WHO group II PH were excluded from the analysis. The optimal cutoff values to classify severe RV enlargement by RVEDV/LVEDV was determined by a receiver operating characteristic (ROC) curve using cardiovascular mortality.

Results:
The event rates for cardiovascular mortality among the OSU and WCH cohorts were 14/42 and 14/58, respectively. Altmayer identified the optimal cut-off as 2.32 (sensitivity = 87.5%; specificity = 87.0%, AUC=82%)
1
. An RVEDV/LVEDV of 2.01 was the optimal cutoff to predict cardiovascular mortality using the ROC analysis from the OSU cohort (sensitivity= 71.4%, specificity = 82.1%, AUC 80.1%). It was 2.46 from the WCH cohort (sensitivity = 64.3%, specificity = 86.3%, AUC 77.7%). When data from the OSU and WCH cohort were combined, the optimal cutoff was 2.1 (sensitivity = 71%, specificity = 72%, AUC 77.1%).

Conclusions:
Using data from three different populations of pcPH patients, an RVEDV/LVEDV of at least >2.0 can be used to partition severe RV dilation using cardiovascular mortality.
Abstract 17127: Rapid Progression of Conduction System Disease in Suspected Fulminant Nivolumab Myocarditis
Authors: Shetty Sanath , Maheshwari Tania , Zarrella Geoffrey C , Palli Vasu
Published: December 2023

Background:
Immune checkpoint inhibitors (ICI) have shown efficacy in treating a wide spectrum of malignancies, but have a known risk of cancer therapy related cardiac toxicity. We present a case that demonstrates how conduction system disease can rapidly progress in a patient with suspected nivolumab (PD1) induced fulminant myocarditis.

Case:
An 82-year-old male with a history of esophageal carcinoma presented with agonal breathing and altered mental status. He had received his second dose of PD1 therapy three days prior. He was intubated and admitted for hypoxic respiratory failure and elevated troponin. His initial EKG demonstrated new marked 1st degree AV block with right bundle branch block (RBBB) morphology. A stat echocardiogram noted an EF of 60-65% with no wall motion abnormalities.

Decision-making:
On Day 2, Mobitz Type I block was appreciated on telemetry. The patient met criteria for acute myocarditis with his clinical presentation, new conduction system disease, and high sensitivity troponin of 13,000. Given recent PD1 therapy, lack of infectious prodrome, and lack of prior heart disease, suspicion for ICI induced myocarditis was high. High dose steroid therapy was initiated. On Day 3, the patient was noted to have alternating left bundle branch block and RBBB. On Day 4, he progressed to complete heart block, prompting transvenous pacemaker (PM) placement with subsequent permanent PM placement. A repeat echo showed global hypokinesis with an EF of 40-45% and reduced RV function. He also required vasopressor support meeting criteria for fulminant myocarditis. Due to his hemodynamic instability and low clinical suspicion, he did not receive cardiac catheterization. Cardiac MRI and cardiac biopsy were not readily available in this institution.

Conclusion:
The clinical findings, lack of infectious prodrome, and worsening arrhythmia requiring pacing and vasopressor support, in patient with recent PD1 treatment suggests nivolumab induced fulminant myocarditis. In institutions without advanced testing infrastructure, rapid recognition of progressive conduction system disease may be used as an early marker for diagnosis, treatment initiation, and referral to tertiary care centers for advanced management of fulminant ICI myocarditis.
Abstract 17132: IRE1α Protects Against Cardiac Fibrosis via Regulating Selective Transcript Degradation
Authors: Parker Sarah N , Sandoval Ernie H , Glembotski Chris C , Blackwood Erik
Published: December 2023

Background:
Upon cardiac injury, cardiac fibroblasts become activated and differentiate intomyofibroblasts to maintain cardiac structure and function through secretion of stabilizingextracellular matrix (ECM) components. However, if this persists, it leads to stiffening of themyocardium and heart failure. The unfolded protein response (UPR) responds to an increaseddemand for folding of nascent secreted ECM proteins trafficked through the endoplasmicreticulum such as collagen. IRE1α, the most evolutionarily conserved arm of the UPR, actsadaptively both by enhancing protein folding of secreted proteins and reducing prolongedincreases in protein synthesis as occurs during pathologic cardiac fibrosis.

Hypothesis:
IRE1α protects against cardiac fibrosis via inhibiting pathologic sustained fibroblastactivation.

Methods:
Primary cardiac fibroblasts (CFBs) were cultured with transforming growth factor beta(TGF-β) to promote activation,
in vitro
. Small molecule targeting approaches were utilized tospecifically inhibit or activate IRE1α. IRE1α-floxed mice were injected with AAV9 to knockoutIRE1α specifically in myofibroblasts (IRE1mfbKO) and were subjected to transverse aorticconstriction (TAC) as a model of heart failure to stimulate fibroblast activation,
in vivo
.

Results:
While small molecule activation of IRE1α significantly blunted CFB activation inresponse to TGF-β, specific inhibition of IRE1α’s endonuclease domain enhanced CFBresponsiveness to TGF-β. Importantly, this effect occurred independent of IRE1α’s canonicalmechanism of activating the transcription factor, XBP1, implicating regulated IRE1α-dependentdecay (RIDD) as a novel anti-fibrotic protective mechanism. Transcriptomics of CFBs identifieda novel “RIDD-ome” of pro-fibrotic mRNA targets of IRE1α-mediated degradation. Finally, inresponse to TAC, IRE1mfbKO mice exhibited an exacerbated decrease in cardiac function andmarked increase interstitial fibrosis.

Conclusions:
IRE1α protects against pathologic differentiation of CFBs in response to TGF-β or TACvia regulating the degradation of a novel subset of pro-fibrotic transcripts. Thus, small moleculetargeting of IRE1α represents a novel approach to mitigating cardiac fibrosis.
Abstract 17136: Prospective Cohort Study for Evaluating the Safety and Efficacy of Mobile, Motorized Enhanced Extracorporeal Counterpulsation in Refractory Angina Patients
Authors: Lee Jooyeon , Oh Jaewon , Kim In-Cheol , Lee Seonhwa , Kim Se-Eun , Lee Chan Joo , Kim Hyungseop , Kang Seok-min
Published: December 2023

Introduction:
Enhanced external counterpulsation (EECP) therapy is a potential treatment for refractory angina, which refers to persistent symptoms despite optimal treatment. However, the immobility, cost, and lack of individualized pressure control limit the accessibility and clinical implications of EECP. To address these limitations, a new Mobile, Motorized Enhanced Counterpulsation (MECP) device has been developed.

Hypothesis:
To investigate efficacy of MECP in improving in angina functional class and exercise tolerance in patients with refractory angina and to validate the consistency in outcomes observed with conventional EECP treatment.

Methods:
This prospective study enrolled patients with symptomatic refractory angina between September 2020 and December 2022 at two tertiary centers in Korea. Baseline and post-treatment assessments included measurements of angina scale, 6-minute walking test, cardiopulmonary exercise test, and central arterial pressure.

Results:
The study included 71 patients (70.4% male, median age 66 years). After the 10-hour MECP treatment session, 57.7% of patients showed improvement in angina scale based on Canadian Cardiovascular Society classification, with a significant distribution change from 76.8% to 49.3% in class II and from 21.7% to 5.7% in class III (p<0.001). Furthermore, patients demonstrated an increase of 20 meters in the 6-minute walk distance after MECP treatment (464 meters vs. 484 meters, p<0.001). However, there were no statistically significant differences in the baseline characteristics of patients based on their response to MECP.
Conclusion
:
Our study highlights the substantial benefits of MECP in relieving symptoms for patients with refractory angina and suggests its potential for broader clinical applications which merits further investigation.
Abstract 17139: Angiopoietin 2 Independently Predicts Heart Failure Hospitalization and is Beneficially Modified by GLP1RA: Results From the EXSCEL Trial
Authors: Harrington Josephine , Nguyen Maggie , Peters Anthony , Felker Michael , Karra Ravi , Sattar Naveed , Sourij Harald , Hernandez Adrian F , Green Jennifer , Mentz Robert J , Holman Rury , Shah Svati H
Published: December 2023

Background:
Higher plasma concentrations of angiopoietin 2 (ANGPT2) are associated with higher risk for hospitalization for heart failure (HF) and death in univariate analyses. However, the independent association of this ANGPT2 after adjustment for clinical factors or clinically available biomarkers is not known.

Methods:
High throughput proteomic profiling was performed using the SomaLogic SomaScan platform in 5473 patients with type 2 diabetes enrolled in the EXSCEL clinical trial of the GLP1RA exenatide vs. placebo who had available biospecimens at baseline. The association between ANGPT2 with time-to-HF hospitalization, MACE, and death was assessed using univariable and multivariable Cox modeling, with adjustment for age, sex, HbA1c, NT-proBNP, hs-TnT, left ventricular ejection fraction, HF etiology and study treatment. These analyses were also performed in the subset of participants living with obesity (BMI >30 kg/m
2
), and those with CKD (CrCl <60ml/min).

Results:
In 5473 EXSCEL trial participants included in this biomarker sub-study, 215 (3.9%) experienced a hospitalization for heart failure, 813 (14.9%) a MACE event and 528 (9.7%) died during a median follow-up of 3.2 years. Relative ANGPT2 concentration was significantly associated with HF hospitalization (aHR 1.70 [95% CI 1.39 to 2.08]), MACE (1.20 [1.07 to 1.35]), and death (aHR 1.21 [1.05 to 1.39]) in univariable and multivariable analyses, including after adjustment for NT-proBNP and TnT (Figure). Exenatide use resulted in significant changes from baseline in ANGPT2 concentrations (p interaction<0.001) (Figure).

Conclusion:
ANGPT2 is predictive of hospitalization for HF, MACE, and death independent of clinical factors including traditional biomarkers of NT-proBNP and TnT. ANGPT2 was beneficially modified by exenatide, a GLP1RA, suggesting a potential role for this biomarker in optimizing HF therapy.
Abstract 17142: Deficiency of Smooth Muscle ADAR1 Exacerbates Vascular Remodeling and Pulmonary Hypertension
Authors: Kim Yunhye , Maroli Giovanni , Woodcock Chen-Shan J , Klouda Tim , Hao Yuan , Liu Tiffany , Schumacher Valerie A , Li Jin B , Raby Benjamin , Chan Stephen , Pullamsetti Soni , Yuan Ke
Published: December 2023

Background:
Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes the conversion of adenosine (A) to inosine (I) in double-stranded RNA, which is critical to prevent auto-inflammatory responses mediated by activation of the type I interferon (IFN) signaling. Here, we define the role of ADAR1-dependent RNA editing in IFNβ activation and pulmonary artery smooth muscle cell (PASMC) remodeling in pulmonary arterial hypertension (PAH), a devastating disease leading to right heart failure and premature death.

Methods:
Total RNAs from IPAH PASMCs (N=3) and healthy control (N=3) were deep sequenced by RNA-seq and determined the fraction of reads with a ‘G’ nucleotide editing sites using RADAR database. A transgenic line

ADAR1
SMC-KO

was generated by knocking down
ADAR1
selectively in αSMA+ cells, followed by 3 weeks of hypoxia. PKR inhibitor Imoxin was used to treat

ADAR1
SMC-KO

.

Results:
SMC layers of human IPAH tissues expressed reduced levels of ADAR1. Moreover, IPAH PASMCs displayed decreased mRNA and protein levels of ADAR1, along with reduced editing sites compared to healthy PASMCs (Fig.1A). The knockdown of ADAR1 in PASMCs resulted in the activation of the MDA5-PKR-IFNβ signaling pathway. Compared with controls
in vivo
, hypoxic

ADAR1
SMC-KO

mice developed severe PH, as evidenced by excessive vascular remodeling in distal arterioles (Fig.1B) and increased vascular leakage resulting in elevated right ventricular systolic pressure (37 vs 23 mmHg) and right ventricular hypertrophy by Fulton Index (46 vs. control 20%) (Fig.1C). The immunofluorescence staining showed higher expression of IFNβ and increased recruitment of inflammatory immune cells. Imoxin treatment prevented PH & RVH.

Conclusions:
The deficiency of ADAR1 leads to the activation of IFNβ thus contributing to the pathological processes observed in PAH. Inhibiting PKR activity could attenuate the aberrant IFNβ activation and potentially serve as a new therapeutic strategy to treat PAH.
Abstract 17143: Lorundrostat for Treatment of Obesity-Related, Aldosterone-Dependent Hypertension - An Endotype-Specific, Targeted Approach to the Treatment of Uncontrolled Hypertension
Authors: Rodman David , Cizman Borut
Published: December 2023

Hyperaldosteronism manifests as low renin hypertension (HTN) with endothelial dysfunction and vascular fibrosis. In the aging vasculature, these pathological changes may be exacerbated by non-genomic aldosterone signaling via GPER (GPR30), which is not inhibited by mineralocorticoid receptor antagonists (MRA). In trials with healthy subjects and patients with uncontrolled HTN, the novel, highly selective aldosterone synthase inhibitor, lorundrostat, reduced median morning plasma aldosterone concentration (PAC) by approximately 70%. PAC reduction was dose-dependent and associated with a mean placebo-adjusted reduction in systolic blood pressure (BP) of -16.7 mmHg (N=15, p<0.01, 90% CI: -25.5 to -7.9 mmHg) and -12.3 mmHg (N=12, p<0.03, 90% CI: -21.6 to -3.1 mmHg) in subjects with body mass index (BMI)
>
30 kg/m
2
receiving 50mg or 100mg QD of lorundrostat, respectively. In contrast, in non-obese individuals, BP reductions were modest and not statistically significant. Salutary BP effects of 100mg QD lorundrostat at week 8 were observed in individuals with normal to high renin (N=30, -11.4 ± 2.5 mmHg) and low renin (N=25, -11.9 ± 2.8 mmHg). Linkage between obesity, HTN and increased aldosterone has been suggested by studies in a mouse model of obesity, hyperleptinemia and HTN. In this model, both leptin receptor blockade and lorundrostat restored normal BP. As anticipated, in the Phase 2 trial, mean serum leptin was elevated at baseline in obese (N=103, 37.8 ± 2.4 ng/mL) v. non-obese (N=88, 21.6 ± 1.9 ng/mL, p<0.001) individuals with uncontrolled HTN and could be a useful biomarker to identify lorundrostat-responsive HTN. MRAs are recommended as fourth-line therapy for resistant HTN. However, MRAs can be associated with hormonal side-effects and stimulate excess aldosterone production that may increase non-genomic signaling, endothelial dysfunction and vessel wall remodeling. Lorundrostat has neither of these liabilities and may be an important new antihypertensive. Renin-independent, leptin- and aldosterone-dependent HTN defines a unique endotype in obese hypertensive individuals. Endotype-targeted therapy may allow early identification, intervention and improved BP control in obese individuals.
Abstract 17147: Hypertriglyceridemia Associated With Peritoneal Dialysis
Authors: Varughese Mini G , Rivas Rios Jose R , Ballantyne Christie M
Published: December 2023

Introduction:
Chronic kidney disease and kidney replacement therapies (KRT) are associated with increased incidence of dyslipidemia and cardiovascular disease. In patients with chronic kidney disease, uremic dyslipidemia can cause qualitative and quantitative changes in the lipoproteins due to inflammation, malnutrition, and proteinuria. The major abnormalities include increase in triglyceride (TG) rich particles and reduced activity of lipoprotein lipase (LP). In this case, we present a patient who developed worsening hypertriglyceridemia after KRT changed to peritoneal dialysis (PD).

Clinical Course:
A 65-year-old female with end stage renal disease (ESRD) on PD, mixed dyslipidemia and hypertension who presented for elevated triglycerides 2084 mg/dL. Patient had been on KRT for 5 years and was switched to PD for the past 3 years. TG prior to starting PD was 203 mg/dL. Patient was started on atorvastatin 40 mg daily, Omega-3 Fatty Acids 2 g twice daily and substituted hypertonic glucose exchange with icodextrin for dialysate. TG improved to 391 mg/dL with these changes.

Discussion:
Hypertriglyceridemia is a common condition with management include lifestyle modifications and medications. In uremic dyslipidemia, there is increase in triglyceride-rich lipoproteins, small dense low-density lipoprotein particles, increased lipoprotein (a), and decreased high density lipoprotein. The pathogenesis of hypertriglyceridemia seen in PD is not well understood. There is overproduction of very low-density lipoprotein, peritoneal protein loss through drained dialysate, carbohydrate loading from the glucose based dialysate and reduced LP function contributing to the hypertriglyceridemia. This patient’s TG worsened when she was switched to PD from hemodialysis. TG improved with lifestyle modifications, medications and change in dialysate fluids. Hypertriglyceridemia associated with PD is rare, but it is important to recognize and treat to reduce risk of pancreatitis and cardiovascular complications.
Abstract 17169: Beyond CHA2DS2-VASc: Independent Predictors of Ischemic Stroke in Patients With Atrial Fibrillation
Authors: Harrington Josephine , Arps Kelly , Wu Angie , Chiswell Karen , May Heidi T , Subash Shantha Ghanshyam Palamaner , VanWormer Jeffrey , Viethen Thomas , Mundl Hardi , Coppolecchia Rosa , Elci Eren , Vaitsiakhovich Tatsiana , Jackson Larry R , Thomas Kevin L , Piccini Jonathan P , Patel Manesh R
Published: December 2023

Introduction:
Factors outside of the CHA
2
DS
2
-VASc score also contribute to stroke risk, and patients prescribed anticoagulants still face a residual stroke risk.

Methods:
A multivariable model to predict stroke risk was built using data from patients treated for atrial fibrillation (AF) at Duke between 2009 and 2018. The model was then refined in patients presenting with incident AF at 7 hospitals within the larger PCORnet database.

Results:
Of 43,896 patients with AF included in our multivariable model creation data set, median age was 71.6 years, 44.2% of patients were female, 17.4% were black, and median CHA
2
DS
2
-VASc was 3. DOAC was prescribed in 24.2%, warfarin in 28.7%, and 50.4% were not prescribed either anticoagulant. The 5-year incidence of ischemic stroke was 3.5%. In a multivariable model, patients who were black, had prior major bleeding, or who were prescribed aspirin or an SSRI were at increased risk for ischemic stroke regardless of type of anticoagulation, whereas lower eGFR did not increase the risk. The model was refined in the PCORnet database using 244,213 patients with incident AF, with additional identification of lower risk for patients with BMI >30 or recent cardiac surgery, and use of P2Y12 as a risk factor. Multivariable models showed substantial improvement in stroke prediction within both the Duke and PCORnet treatment cohorts, with improvement in C-indices to 69.6-75.7%, from baseline C-indices of 63.5%-68.7% for CHA
2
DS
2
-VASc alone among patients on DOAC, warfarin, or who were untreated.

Conclusions:
Lower BMI, prior major bleeding, antiplatelet (ASA or P2Y12) use, and black race were significantly associated with increased risk for ischemic stroke, independent of the commonly used CHA
2
DS
2
-VASc score. Future AF research should attempt to integrate these emerging risk factors with the existing CHA
2
DS
2
-VASc framework to improve the identification of patients at high risk of stroke and in greatest need of anticoagulation.
Abstract 17185: Percutaneous Intervention in Chronic Total Coronary Occlusion: Impact on Ventricular Arrhythmia and Mortality Compared to Medical Therapy
Authors: jabri ahmad , Alhuneafat Laith , Alameh Anas , Alqarqaz Mohammad , Soltero Enrique , Basir Mir B , Yousaf Adnan , Karim Saima , Siraj Aisha
Published: December 2023

Background:
The incidence of ventricular arrhythmias (VA) in patients with chronic total coronary occlusions (CTO) in the absence of advanced left ventricular dysfunction is not well described. Moreover, little is known about how revascularization may impact VA in this population compared to medical therapy alone.

Methods:
In this single-center retrospective cohort study from January 2010 to January 2019. We identified 100 patients with CTO on cardiac catheterization with a left ventricular ejection fraction (LVEF) >35% who did not undergo coronary artery bypass surgery following CTO diagnosis. Percutaneous revascularization was performed for 44 patients. The primary outcomes evaluated were VA and mortality rates at end of the study period. Secondarily, cardiovascular outcomes were compared between the intervention and optimal medical therapy (OMT) groups at the end of the study period. Survival analysis was performed via Kaplan Meier calculation for VA and mortality. Statistical analysis was performed using STATA 15 and R-studio.

Results:
Mean age was 59.91(± 13.05) and BMI was 31.8(± 7.41). Patients were 66% male, 64% White, and 23% Black. Baseline characteristics, use of antiarrhythmic therapy, baseline LVEF, and the number of CTOs and locations of CTOs were not significantly different between groups. During a median follow-up of 4.1(± 2.54) years, the OMT group experienced higher rates of VA (21.4% vs 7.7 %, p = 0.011), and mortality (37.5% vs 15.9%, p=0.031).

Conclusion:
CTO in the absence of severe LV systolic dysfunction (LVEF <35%) is associated with a high rate of VA and all-cause mortality, suggesting the need for further study on the impact of CTOs and their revascularization on VA and mortality in patients with LVEF >35%.
Abstract 17196: Genetic and Acquired DHCR7 Deficiency Upregulates 7β-hydroxycholesterol to Drive Endothelial Apoptosis and Pulmonary Hypertension
Authors: Rao Rashmi J , Kim Hee-Jung , Jiang Siyi , Tai Yi-Yin , Wang Bing , Tang Ying , El Khoury Wadih , Kirillova Anna , Al Aaraj Yassmin , Watson Annie , Sharma Ankit X , McDonald Jeffrey , Francis Kevin , Ramachandra Rao Sriganesh , Fliesler Steven J , Bertero Thomas , Sun Wei , Harvey Lloyd D , Chan Stephen Y
Published: December 2023

Introduction:
Pulmonary hypertension (PH) is a fatal disease without a cure, in which endothelial dysfunction drives pathologic remodeling of the pulmonary vasculature. Individuals with Smith-Lemli-Opitz syndrome (SLOS) develop PH, but the underlying mechanisms remain undefined. SLOS is an autosomal recessive disorder of cholesterol synthesis, resulting from loss-of-function mutations in 7-dehydrocholesterol reductase (DHCR7)-the terminal enzyme in the
de novo
synthesis of cholesterol- that leads to accumulation of 7-dehydrocholesterol (7-DHC) and cytotoxic oxysterol species. The role of DHCR7 in PH, however, is unknown.

Hypothesis:
Elevated cytotoxic oxysterols resulting from genetic or acquired DHCR7 deficiency promotes endothelial dysfunction and the development of PH.

Methods & Results:
DHCR7 mRNA and protein expression was decreased in pulmonary artery endothelial cells (ECs) in cellular (P=0.0089), rodent, and human PH models, mirroring DHCR7 reduction in SLOS. Both genetic loss of DHCR7 and hypoxia promoted a global shutdown of
de novo
cholesterol synthesis, resulting in an accumulation of cholesterol intermediates and increased derivative oxysterols. Specifically, 7β-hydroxycholesterol (7β-HC) was elevated in DHCR7-deficient ECs (P<0.0001), and 7β-HC drove endothelial apoptosis (P<0.0001) via downregulation of insulin-like growth factor 1 (IGF1) in ECs (fold change=0.101 ± 0.034, FDR=6.65E-11). Conversely, overexpression of DHCR7 upregulated IGF1 expression (P<0.0007), and IGF1 delivery reversed apoptosis (P<0.0001). Correspondingly, ECs derived from SLOS patient stem cells with DHCR7 mutations (p.T93M/c.964-1G>C) exhibited IGF1-dependent apoptosis. Finally, EC-specific DHCR7 deletion in chronically hypoxic mice induced more severe PH
in vivo
(right ventricular systolic pressure 36.4 mmHg vs. 30.8 mmHg, P<0.0130).

Conclusions:
Resulting either from hypoxic or genetic causes, DHCR7 deficiency promoted EC apoptosis and PH via 7β-HC accumulation and subsequent IGF1 downregulation. Our work is the first to define an oxysterol-dependent mechanism underlying the link between genetic and acquired DHCR7 deficiency and PH.
Abstract 17197: Team-Based Care for Uncontrolled Hypertension in Accountable Care Organizations: A Simulation Study
Authors: Rao Aditi S , Sawant Vaishnavi , Zhang Yiyi , Krousel-wood Marie A , Nuckols Teryl , Ye Siqin , Ebinger Joseph E , Bryant Kelsey , Moran Andrew E , Bellows Brandon K
Published: December 2023

Background and Objectives:
Team-based care (TBC) is associated with greater blood pressure (BP) reductions than usual care, particularly when non-physicians titrate antihypertensive medications, but has yet to be widely adopted. This analysis projected the effectiveness of TBC among patients with uncontrolled hypertension from three accountable care organizations (ACOs): Columbia University Medical Center (New York), Cedars-Sinai Medical Center (California), and Ochsner Accountable Care Network (Louisiana).

Methods:
The Cardiovascular Disease (CVD) Policy Model is a computer model that simulates modifiable hypertension care processes (i.e., office visit frequency, BP measurement accuracy, medication intensification, and patient medication adherence) and has been validated to reproduce TBC outcomes. We used the CVD Policy Model to simulate the ACO population aged >=65 years with BP >=140/90 mmHg at two outpatient visits in 2015, and project BP and CVD outcomes out to 10 years with usual care alone vs. one year of TBC followed by a return to usual care. Hypertension usual care processes were derived from national sources and published literature. The model was calibrated to reproduce systolic BP reductions with TBC at one year vs. usual care from a published meta-analysis, which were stratified by the team member responsible for antihypertensive medication titration: -5.0 (95%CI -7.9, -2.2) mmHg with physician titration and -10.5 (95%CI -16.2, -4.8) mmHg with non-physician titration.

Results:
The ACO population with uncontrolled BP (N=9,788) had a mean (SD) age of 76.3 (7.8) years; 66.6% were white and 59.8% female. The mean BP (SD) at baseline was 151.1 (13.0)/78.1 (10.6) mmHg and 39.1% had a history of CVD. Compared with usual care at 10 years, TBC with non-physician titration was projected to increase the proportion with BP <140/90 mmHg by 16.0% and TBC with physician titration by 4.2%. Relative to usual care, TBC with non-physician titration was projected to prevent 20.8 CVD events per 1000 individuals and TBC with physician titration to prevent 6.6 CVD events.

Conclusion:
Universal adoption of TBC, especially with non-physician titration, could improve achievement of quality benchmark BP control goals and prevent CVD events in ACO populations.