bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11466: CBSCs Derived Extracellular Vesicles Modify the Immune Response After Cardiac Ischemic Injury to Enhance Repair
Authors: Yang Yijun , Johnson Jaslyn , Troupes Constantine D , Feldsott Eric A , Kraus Lindsay , Megill Emily , Eaton Deborah M , Wang Tao , Wagner Marcus , Ma Lena , Wallner Markus , KUBO Hajime , Kino Tabito , Berretta Remus M , Khan Mohsin , Kishore Raj , Houser Steven R , Mohsin Sadia
Published: June 2023

Introduction:
Few therapies have produced significant improvement in cardiac function after ischemic cardiac injury (ICI). The activation of local inflammatory responses is critical to cardiac repair after ICI. Our previous studies showed that cortical bone derived stem cells (CBSCs) possess can enhance repair after ICI. Beneficial effects of CBSCs appear to be mediated by paracrine factors including extracellular vesicles (EVs). This study explored if and how these EVs enhance cardiac repair by modulating the ICI immune response.

Hypothesis:
CBSCs derived extracellular vesicles (CBSC-EV) modulate immune response after ICI.

Methods and Results:
Both CBSCs and CBSC-EV were transplanted into mice after myocardial infarction (MI). CBSCs and CBSC-EV treated animals had better ICI repair compared with Saline, with reduced scar size, attenuated structural remodeling, improved cardiac function, and reduced cell apoptosis. These effects were linked to alteration of immune response. Plasma analysis of CBSCs and CBSC-EV treated animals showed significantly lower level of pro-inflammatory cytokines such as TNFα 24 hours after MI. CBSCs and CBSC-EV treatment induced significant polarization from CD86+ M1 macrophages towards CD206+ M2 macrophages phenotype 5 days post-MI, with subsequent reduction of CD8+ T cells and increase of CD4+ T cells, especially the FoxP3+ Treg population, from 7 days to 14 days post-MI. RNA sequencing analysis revealed that CBSC-EV contained a distinct transcriptome compared with endothelial progenitor cells and cardiosphere-derived cells. Gene Ontology analysis suggested the differentially expressed genes in CBSC-EV significantly enriched in immune cell receptor binding. MiR-182 and miR-183, which ranked top of the most significantly upregulated genes in CBSC-EV, attenuated M1 macrophage polarization after LPS treatment and promote CD25+ FoxP3+ Treg differentiation in vitro.

Conclusions:
CBSC-EV enhance cardiac repair by modulating the immune response after injury and highlight the molecular bases of into the beneficial effects of cell-free therapy after ICI.
Abstract 11469: Effects of Metformin and Donepezil on the Prevention of Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patient: A Randomized Controlled Trial
Authors: Osataphan Nichanan , Apaijai Nattayaporn , Phrommintikul Arintaya , LEEMASAWAT KRIT , Somwangprasert Areewan , Suksai Supanai , Chattipakorn Siriporn , Chattipakorn Nipon
Published: June 2023

Introduction:
Cardiotoxicity from doxorubicin (DOX) is the most concerning adverse event. Although data from preclinical studies showed that metformin and donepezil prevented myocardial injury and preserved mitochondrial function against DOX-induced cardiotoxicity, the beneficial effects of these drugs in clinical trial have not been established.

Hypothesis:
Oral administration with metformin or donepezil prior receiving DOX prevents DOX-induced cardiotoxicity in breast cancer patients.

Methods:
In this double-blind, placebo-controlled trial. We randomly assigned 111 female breast cancer patients to receive oral metformin 2000 mg (n=40), donepezil 10 mg (n=31), or placebo (n=40), once daily 1 day prior to DOX and continued during DOX treatment. Blood samples were obtained at baseline, after chemotherapy cycle 2 and 4. The primary outcome was the change of troponin-I (trop-I) from baseline. The secondary outcomes were the change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline, and mitochondrial function in the peripheral blood mononuclear cells.

Results:
Baseline characteristics were similar between the groups, mean age was 51.93±10.45 years. The mean trop-I changed from baseline were 29.97±4.59 pg/ml in placebo group, 31.07±7.28 pg/ml in metformin group (p = 0.90 vs. placebo) and 30.97±5.07 pg/ml in donepezil group (p = 0.88 vs. placebo). The changes of NT-proBNP level and mitochondrial oxidative stress were comparable between placebo vs. metformin or donepezil groups. However, donepezil significantly decreased mitochondrial mass and mitochondrial maximal respiration after chemotherapy (Figure).

Conclusion:
In breast cancer patients undergoing chemotherapeutic treatment with DOX, metformin and donepezil did not prevent myocardial injury. Treatment with donepezil resulted in the decrease in mitochondrial mass and maximal respiration following chemotherapy that might caution its use in breast cancer.
Abstract 11477: Assessing New Onset of Atrial Arrhythmia in Patients Undergoing Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy
Authors: Moore Ryan , Silkowski Molly , Mostertz William C , Evans Matthew , Nielsen Chris , Fernandes VALERIAN
Published: June 2023

Introduction:
Alcohol septal ablation (ASA) is an effective percutaneous procedure used to treat refractory hypertrophic obstructive cardiomyopathy (HOCM). ASA relieves left ventricular outflow tract (LVOT) obstruction by creating a targeted infarction in the septal muscle. Diastolic dysfunction and mitral regurgitation are responsible for increased left atrial pressure which contributes to left atrial ectopy. We seek to assess the incidence of atrial arrhythmias post-ASA and identify predictors to risk stratify these patients.

Methods:
Using a patient database maintained internally, 144 consecutive patients who underwent ASA for HOCM between March 2017 and February of 2022 at MUSC were retrospectively reviewed. Patients were selected based on the need for cardiac event monitoring after ASA. Patients were retrospectively analyzed for a previous history of atrial fibrillation (AF) as well as a new onset of AF after ASA. SPSS statistics was used for statistical analysis.

Results:
A total of 31 patients met final inclusion criteria. During the monitored time, seven patients (22.58%) developed a new onset of AF after ASA. Patients who developed AF post-ASA were found to have a statistically higher left atrial end-systolic volume index (LAESVi, mL/m
2
) and left ventricular end-diastolic pressure (LVEDP, mmHg) (59.96 ± 8.93, 34.33 ± 11.54) when compared to those who did not develop AF (41.13 ± 13.93, 23.33 ± 9.06 (p=0.0003, p=0.0331)).

Conclusions:
In this high-risk proportion of patients who required cardiac monitoring post-ASA, there is a higher-than-expected risk for new onset of AF. The left atrial size and left ventricular filling pressures before ablation were the only significant predictors for development of atrial arrhythmias after ASA. Longer-term evaluation will be able to address if the expected reduction in atrial size and LVOT gradient after ASA will reduce the overall long-term burden of atrial arrhythmias.
Abstract 11480: Telmisartan to Improve Walking Performance in People With Lower Extremity Peripheral Artery Disease: The Telex Randomized Clinical Trial
Authors: McDermott Mary M , Bazzano Lydia , Peterson Charlotte A , Sufit Robert , Ferrucci Luigi , Zhao Lihui , Polonsky Tamar S , Zhang Dongxue , Domanchuk Kathryn , Lloyd-Jones Donald , Leeuwenburgh Christiaan , Guralnik Jack , Kibbe Melina R , Kosmac Kate , Criqui Michael H , Tian Lu
Published: June 2023

BACKGROUND.
People with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan, an angiotensin receptor blocker (ARB), has properties that reverse these abnormalities. This randomized clinical trial tested whether telmisartan improved six-minute walk distance, compared to placebo, in people with PAD at 6-month follow-up.

METHODS.
This multi-centered randomized clinical trial was designed as a 2 x 2 factorial design, comparing the effects of telmisartan plus supervised exercise therapy (SET) to telmisartan alone and SET alone, respectively and comparing telmisartan alone to placebo. PAD participants were randomized to one of four groups: telmisartan+SET (N=30), telmisartan + attention control (N=29), placebo + SET (N=28), or placebo+ attention control (N=27) for six months. Due to slower than anticipated enrollment, the primary comparison was changed to a comparison of the two telmisartan groups combined to the two placebo groups combined. The primary outcome was 6-month change in 6-minute walk distance. Secondary outcomes were maximal treadmill walking distance, the Walking Impairment Questionnaire distance, speed, and stair climbing scores, and the short-form 36 physical functioning score. Results adjusted for site, baseline six-minute walk distance, randomization to SET vs. attention control, and group differences in the prevalence of sex and heart failure at baseline.

RESULTS.
Of 114 randomized patients (mean [SD] age, 67.3 [9.9] years, 46 (40.4%) female, 81 (71.1%) Black), 105 (92%) completed 6-month follow-up. See the Table for results.

CONCLUSIONS.
These results do not support telmisartan for improving objectively measured walking performance or patient reported outcomes in patients with PAD.
Abstract 11511: Stem Cell-Derived Exosome Nebulization Therapy (SCENT) Promotes Cardiac Repair After Myocardial Infarction by Inhibiting CD36
Authors: Li Junlang , Sun Shenghuan , ZHU DASHUAI , Butte Atul , Cheng Ke
Published: June 2023

Introduction:
Stem cell-derived exosomes are promising therapeutics for cardiac repair after injury. Since they have short half-life in vivo, efficient exosome therapies need repeated dosing. Here, we develop a noninvasive and repeatable method for exosome delivery via a nebulizer after myocardial infarction (MI), named
Stem Cell-Derived Exosome Nebulization Therapy (SCENT).

Methods:
Lung spheroid cell-derived-exosomes were isolated from secretome by ultrafiltration and characterized by a Zetasizer. We labelled them with a NIR-680 dye, before delivering them to C57BL/6 mice with MI model via a nebulizer for 7 consecutive days. IVIS live imaging and fluorescent microscopy was used to detect the biodistribution of exosomes in vivo and ex vivo. Echocardiographies were performed to monitor the cardiac function after SCENT in MI mouse and histological analysis helped investigating the myocardial repair, in comparison with the controls. Single-cell sequencing of the whole heart was performed to explore the mechanism of action after SCENT.

Results:
Homing of exosomes to the ischemic heart after SCENT was detected by immunofluorescence microscopy
(Fig. 1a).
SCENT led to significantly improved left ventricular function to our mouse MI model at 2 weeks (EF: 66.97 ± 2.49%), compared to that of MI control (EF: 36.13 ± 3.57%)
(Fig. 1b)
, along with reduced infarct size
(Fig. 1c).
Single-cell sequencing revealed a significant downregulation of CD36 in cardiac endothelial cells, which suppressed the transport and uptake of fatty acids in myocardium, leading to a compensatory increase in glucose utilization and cardiomyocyte proliferation
(Fig. 1d,e)
.

Conclusions:
Exosomes delivered by SCENT were recruited to the ischemic heart, which promoted function recovery and cardiac repair in a mouse MI model. This therapeutic effect was attributed to the inhibition of endothelial CD36. SCENT gives a promising solution for the repeatable and noninvasive treatment for heart repair.
Abstract 11515: Mannose-Binding Lectin is Dysregulated in Cardiac Endothelial Cells of Women With Peripartum Cardiomyopathy
Authors: Aryan Zahra , Moghadami Siavash , Wang Wei , Sadoshima Junichi
Published: June 2023

Introduction:
Peripartum cardiomyopathy (PPCM) is a type of heart failure that presents with systolic dysfunction in the third trimester of pregnancy or early postpartum. Viral myocarditis, genetic predisposition, and hormonal changes are suggested as contributing factors to PPCM. However, the molecular basis of PPCM remained elusive.

Hypothesis:
Cardiac expression of genes involved in immune system response is dysregulated in PPCM.

Methods:
We identified women with PPCM and age/race-matched heart donors from a dataset obtained from Myocardial Applied Genomics Network (MAGNet) consortium. Left ventricular (LV) biopsies were taken at the time of heart transplantation. Bulk RNA-seq was performed on LV tissue of patients with PPCM and non-failing heart donors (NF). We used the Human Cell Atlas (HCA) reference database with accession code ERP128138 to investigate cell-specific enrichment of genes.

Results:
Mean age of study participants was 36.1 years and 33.3% of participants had African American ancestry. We found that
LCN6
(Log2(fold_change) = -4.1, p-val = 0.0027) and
FCN3
(Log2(fold_change) = -3.4, p-val = 0.0042) are downregulated in LV tissue obtained from PPCM compared to NF.
LCN6
encodes lipocalin-6 and
FCN3
encodes ficolin-3 which are upstream of the mannose-binding lectin complement pathway. Based on HCA dataset on adult human hearts, we observed that
LCN6
and
FCN3
genes are mainly expressed by endothelial cells.

Conclusions:
We demonstrated that expression of
LCN6
and
FCN3
genes, which are upstream of the mannose-binding lectin pathway, is decreased in cardiac endothelial cells of individuals with

PPCM. Mannose-binding lectin is a soluble pattern recognition receptor that identifies mannose and N-acetylglucosamine residues in a wide variety of pathogens and antigen-antibody complexes and works as an opsonin that facilitates phagocytosis. Our findings suggest the possibility of impaired immune complex clearance in PPCM pathogenesis.
Abstract 11532: Cardiac Complications in Polyarteritis Nodosa: A Case of Multi-Vessel Coronary Occlusion Treated With 4-Vessel Coronary Artery Bypass Grafting
Authors: Walter Dylan J , Bigham Grace E , Lahti Steven J , Cohen Jeffrey E , Haider Syed W
Published: June 2023

Polyarteritis nodosa (PAN) is a necrotizing vasculitis causing intimal proliferation, luminal narrowing, thrombosis, ischemia, and even infarction. Coronary manifestations are rare, though recent evidence suggests coronary disease may progress rapidly causing significant morbidity and mortality. We report a case of multi-vessel occlusive coronary artery disease (CAD) in a patient with systemic PAN, successfully managed with 4-vessel coronary artery bypass grafting (CABG).

An obese 53-year-old male with hypertension, hyperlipidemia, and tobacco use presented with episodic epigastric pain. Serial troponins and EKGs did not suggest cardiac ischemia. Cardiac MRI showed concentric LV hypertrophy with preserved systolic function without signs of infiltrative disease or fibrosis. Abdominal CT demonstrated splenic infarction, luminal narrowing of the celiac axis, and abdominal aortic and bilateral iliac artery aneurysms. MRA revealed inflammation of the celiac, splenic, and common hepatic arteries. CT angiography revealed beading of the superior mesenteric artery and celiac trunk, indicative of vasculitis. C3 and C4 levels were elevated. Polyarteritis nodosa was felt to be his unifying diagnosis. Prior to initiating cyclophosphamide, he returned with severe epigastric pain prompting admission. Endoscopy was negative. Coronary CT showed extensive calcification. Angiography revealed multi-vessel occlusive disease patterned with ectasia. He underwent 4-vessel CABG revascularization with LIMA-LAD and SVG-OM-LPDA-RPDA. After surgery, he began prednisone, dual anti-platelet, statin, beta-blocker, and angiotensin receptor blockade with rheumatology follow-up for optimal timing of cyclophosphamide initiation.

For patients with systemic inflammatory conditions, recognition of atypical anginal events is crucial as typical identifiers of atherosclerosis may not be obvious. Bypass is definitive therapy, as stenting arteritic vessels may result in neo-endothelization. Clinicians must recognize increased risk of CAD while offering appropriate primary and secondary interventions such as screening imaging and knowledge of disease distribution for appropriate graft choice.
Abstract 11535: Eicosanoid Metabolites Associations With Pulmonary Hypertension
Authors: Roshandelpoor Athar , McNeill Jenna , Choudhary Arrush , Alotaibi Mona , Jain Mohit , Cheng Susan , Lewis Gregory , Ho Jennifer E
Published: June 2023

Introduction:
Systemic inflammation may play a central role in development of pulmonary hypertension (PH). We examined the association of eicosanoid metabolites (upstream regulators of pro- and anti-inflammatory activity) with PH. We hypothesized that multi-site sampling would reveal transpulmonary release or uptake of specific PH-associated eicosanoids.

Methods:
We studied 482 patients with preserved LVEF who underwent right heart catheterization. PH was defined as mean pulmonary artery pressure >20mmHg. Eicosanoid metabolites (n=888) were assessed using a mass spectrometry-based platform. We examined the association of eicosanoids with PH status using multivariable logistic regression. Multi-site sampling from radial and pulmonary arteries was conducted and differences assessed using paired t-tests. Analyses were deemed significant at FDR q<0.05.

Results:
Among 482 patients (56±16 years, 62% women), 200 (41%) had PH. Of 888 eicosanoids, 59 were associated with PH (FDR q<0.05; p<0.004 for all). Of these, 38 were known eicosanoid metabolites/classes and the rest were novel eicosanoids. Known metabolites including linoleic acid (12,13 EpOME) and eicosapentaenoic acid derivatives (11[12]-EpETE) were associated with lower odds of PH; by contrast leukotriene (LTB4) and arachidonic acid derivatives (11,12 diHETrE) were associated with higher odds of PH. Eighteen of 59 observed eicosanoids had concomitant transpulmonary gradients (Figure; FDR q<0.05; p<0.003 for all). Most metabolites associated with higher odds of PH displayed transpulmonary uptake, and those with lower odds of PH displayed transpulmonary release.

Conclusions:
We found specific eicosanoid metabolites including linoleic acid derivatives, thromboxanes, and leukotrienes were associated with PH. Further, transpulmonary gradients indicated potential physiologic relevance. Further studies are needed to elucidate the role of specific eicosanoids in the pathogenesis of PH.
Abstract 11537: IGF-1 Reduces Atherosclerosis in Rapacz Pigs
Authors: sukhanov sergiy , Higashi Yusuke , Danchuk Svitlana , Alfortish Mitzi , Goodchild Traci , Scarborough Amy , Sharp Thomas E , GARCIA DANIEL C , Jenkins James S , Schumacher Jeffrey , Ivey Jan , Tharp Darla , Bowles Douglas K , Lefer David J , Delafontaine Patrice
Published: June 2023

Introduction:
Cardiovascular disease, including atherosclerosis is the leading cause of mortality in the Western world. We have reported that insulin-like growth factor I (IGF-1) reduced atherosclerosis in the murine model, however it is unknown whether IGF-1 exerts protective effect on human-like atherosclerosis.

Hypothesis:
Rapacz pigs with familial hypercholesterolemia (FH pigs) fed with high-cholesterol diet develop human-like advanced plaques in coronary arteries. We hypothesize that IGF-1 suppresses atherosclerosis in FH pigs.

Methods:
Human recombinant
IGF-1 (
50 ug/kg) or saline (control) was injected daily into high-fat diet fed FH swine (n=9/group) for 6 months. Atherosclerotic burden was quantified by intravascular ultrasound (IVUS) at basal level (T0), after 3 months on diet (T3) and at sacrificing (T6).

Results:
IGF-1-injected pigs had 2.6-fold increase in total plasma IGF-1 (ELISA, p<0.001 vs. control pigs). Pigs in IGF-1 and control groups had a gradual increase in vessel volume in the right coronary artery (RCA), and left anterior descending artery (LAD) with time as quantified by IVUS. However, IGF-1-injected pigs had a larger increase in vessel volume after 3 and 6 months compared to controls suggesting vascular hypertrophy. The atherosclerotic burden was increased in RCA, and LAD in both groups after 3 and 6 months of injections compared to the pre-injection time point. We found a significant reduction in atherosclerotic burden in RCA and LAD in IGF-1 group compared to control at 6 months’ time-point (RCA: IGF-1, 203±13%, vs. control, 244±8; LAD: IGF-1, 200±6%, vs. control, 228±11%). The lumen volume of coronaries was decreased in both groups, however, coronaries in IGF-1-injected pigs had on average 24±3% larger lumen volume compared to control pigs at 6 months’ time-point.

Conclusions:
We found that IGF-1 increased total volume of pig coronaries suggesting hypertrophy and these data are consistent with growth-stimulating effects of IGF-1. We found reduction in atherosclerotic burden and increase in lumen volume in coronaries in the IGF-1 group after 6 months of injections consistent with an anti-atherosclerotic effect of IGF-1. Our data support the feasibility of using IGF-1 for as an anti-atherogenic therapy.
Abstract 11547: Red Blood Cell Distribution Width as a Predictive Indicator for Readmissions in Patients With Pulmonary Hypertension
Authors: Jain Akhil , Sreemantula Harsha Sai , Rashid Rakin , SHAIK AISHA SULTANA , Deshpande Sohiel , Ahmed Ibrahim , Sakhineti Sri Sravya Sakhi , Aiya Utsav , Abdul Sattar Aisha , Naik Mansi , Baralo Bohdan , Finley John
Published: June 2023

Introduction:
Elevated red cell distribution width (RDW) has been established as a predictive biomarker in patients with pulmonary hypertension (PH). Its value in predicting readmission rates in PH is not fully understood.

Methods:
PH patients were retrospectively identified between 1/1/2016 and 12/31/2017 and divided into normal (11.5-14.5%) and elevated (>14.5%) RDW. The primary outcome was 90-day readmission related to heart failure (HF) exacerbation, increased supplemental oxygen (O2) requirements, and systemic inflammatory response syndrome (SIRS). Kaplan Meier survival curves were developed for the probability of primary outcomes-related readmissions.

Results:
Index admissions (n=74) had 78.38% elevated RDW (n=58) and 21.62% normal RDW (n=16). Age, sex, race and comorbidities were matched between the 2 cohorts (Figure 1). Of these, 70.3% (n=52) had readmissions in 90-days; 67.2% (n=39) with elevated RDW and 81.2% (n=13) with normal RDW. Log-rank p for 90-day readmission probability for HF exacerbation, increased O2 requirement and SIRS were statistically non-significant 0.945, 0.0931, and 0.351 respectively (Figure 2).

Conclusions:
Our findings do not support RDW alone as a predictive biomarker for readmission in patients with PH, albeit in a small sample size. This study could be viewed as a hypothesis-generating research to spawn further larger studies.
Abstract 11549: Neighborhood Racial Segregation and Access to Transcatheter Aortic Valve Implantation Among Medicare Fee-for-Service Beneficiaries
Authors: Sevilla-Cazes Jonathan , Almarzooq Zaid , Kyalwazi Ashley , Wang Yun , Strom Jordan B , Wadhera Rishi , Yeh Robert W
Published: June 2023

Introduction:
Lower rates of transcatheter aortic valve implantation (TAVI) among Black individuals have been observed, the drivers of this disparity remain poorly understood. We studied the association between county-level racial segregation and rates of aortic stenosis (AS) diagnosis and management.

Methods:
We identified Black and white Medicare fee-for-service beneficiaries living in metropolitan areas between 2016 and 2019. Using the American Community Survey’s residential segregation index (SI), a measure of geographic distribution of Black and white residents ranging from 0 (complete integration) to 100 (complete segregation), we determined segregation in each beneficiaries’ county of residence. We calculated population-level rates of AS diagnosis and TAVI using validated ICD-10 codes. Using hierarchical modeling, we determined the association between racial segregation and rates of AS diagnosis, TAVI receipt, and 30-day mortality.

Results:
A total of 29,264,075 beneficiaries were included in the analysis. Living in a high-segregation county (SI>60) was associated with increased rates of AS diagnosis overall (adjusted OR 1.03 95%CI 1.02-1.03) but no difference in TAVI. However, among Black beneficiaries, increasing county-level segregation was associated with decreased rates of AS diagnosis and TAVI; the opposite association was observed among white beneficiaries (
Figure 1
). Among those with an AS diagnosis, the interaction between Black race and segregation, and lower rates of TAVI persisted (interaction p-value 0.003). Segregation and race were not independently associated with 30-day mortality.

Conclusions:
Living in a high-segregation county is independently associated with decreased population-level rates of AS diagnosis and receipt of TAVI for Black, but not white, individuals. Among Black people living in high-segregation counties, disparities in TAVI rates are associated with decreased AS diagnosis and access to TAVI.
Abstract 11565: Improvement in Cardiopulmonary Function in a Rat Model of Pulmonary Arterial Hypertension Observed With RKER-012, a Novel Activin Receptor Type II Ligand Trap, was Associated With Reduced Markers of Inflammation and Fibrosis in the Right Ventricle
Authors: Materna Chris , Babbs Keith , Kaplan Nathan , Fisher ffolliott , Seehra Jasbir , Lachey Jennifer
Published: June 2023

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance, impaired cardiac output, and right ventricle (RV) overload. PAH is associated with imbalanced TGF-ß signaling, marked by elevated SMAD2/3 signaling, which is associated with inflammation and fibrosis contributing to heart failure. Initially, the RV can compensate for increased pressure due to its adaptive contractility, but chronic pressure overload leads to maladaptive RV remodeling through inflammatory and fibrotic pathways. Current therapies for PAH are primarily vasodilators which do not treat the underlying pathology. RKER-012 is a research form of KER-012, an investigational modified ActRIIB ligand trap designed to inhibit signaling through SMAD2/3. We investigated RKER-012’s mechanism of prevention of cardiac pathology in a Sugen/Hypoxia (SH) PAH model. Rats received a subcutaneous (SQ) dose of 25 mg/kg Sugen 5416 under hypoxic conditions. For 3 weeks, SH rats received vehicle (SH-VEH) or 10 mg/kg RKER-012 (SH-RKER-012) twice weekly SQ. Control rats received VEH twice weekly in normoxic conditions. Systolic pulmonary arterial pressure (sPAP) and Fulton index (FI) were measured. qPCR of RV tissue was used to evaluate the mechanism of RKER-012 in this model. SH-VEH rats had increased FI and sPAP (both p≤0.0001) compared to NX, consistent with development of cardiac and pulmonary impairment. Relative to SH-VEH, RKER-012 reduced increased FIand prevented increased sPAP (both p≤0.001) in SH rats so that sPAP did not differ from NX. Relative to NX, SH-VEH had increased RV expression of fibrotic markers such as Timp1, Col1a1, Col3a1, Runx2, and LOX (all p≤0.05). In contrast, SH-RKER-012 rats had reduced expression of Timp1, Col1a1, Col3a1, Runx2 and LOX (all p≤0.05) relative to SH-VEH. Inflammation markers CD68 and MCP1 (both p≤0.05) were increased in SH-VEH compared to NX. CD68 expression was reduced in SH-RKER-012 (p≤0.01) compared to NX but MCP1 expression was not affected (p=0.54). These results support that RKER-012 attenuated upregulation of key inflammation and fibrosis markers in a PAH preclinical model and suggest that KER-012 has a distinct mechanism from vasodilation and could be developed as a cardioprotective treatment for PAH.
Abstract 11576: Association Between Pre-Operative Right Heart Catheterization Parameters and Outcomes in Isolated Coronary Artery Bypass Grafting
Authors: Hameed Irbaz , Amabile Andrea , Li Eric S , Yalcintepe Doruk , Martz Sulague Ralf , Effiom Victory B , Larson Haleigh , Geirsson Arnar , Williams Matthew
Published: June 2023

Objective
We evaluate the association between pre-operative right heart catheterization variables and outcomes in patients undergoing isolated coronary artery bypass grafting (CABG).

Methods:
All patients undergoing isolated CABG at our institution from 2013-2021 who also underwent pre-operative right heart catheterization <14 days prior to isolated CABG were retrospectively queried. The primary outcome was operative mortality. Secondary outcomes were post-operative myocardial infarction, stroke, need for dialysis, duration of intensive care unit (ICU) stay, and duration of inotropic support.

Results:
Seventy-eight patients were analyzed. The incidence of operative mortality was 8(10.3%). The incidence of the secondary outcomes was 7(9.0%) for myocardial infarction, 5(6.4%) for stroke, and 4(5.1%) for need of dialysis. The median duration of ICU stay and inotropic support were 4[3.0, 7.8] and 2[1.3, 4.0] days respectively. On multivariable regression, central venous pressure was significantly associated with operative mortality (odds ratio (OR) 1.14, 95%CI 1.02-1.27, p=0.02) and duration of inotropic support (OR 1.02, 95%CI 1.00-1.03, p=0.04). Preoperative cardiac index was also significantly inversely associated with duration of ICU stay (OR 0.72, 95%CI 0.62-0.84, p<0.001) and inotropic support (OR 0.76, 95%CI 0.63-0.92, p<0.01).

Conclusion
Despite inclusion of cardiogenic shock in STS-PROM, baseline central venous pressure and cardiac index are independently associated with operative mortality, inotrope requirement and duration of ICU stay in patients undergoing isolated CABG. Assessment of pre-operative right heart function by right heart catheterization should be considered in this high-risk population to guide pre-operative optimization and intra-/post-operative decision-making.
Abstract 11577: Disparities in One-Year Mortality Among Infants With Cyanotic Congenital Heart Disease - Insights From Contemporary National Data
Authors: Steurer Martina A , McCulloch Charles , Santana Stephanie , Collins james , Branche Tonia , Jelliffe-Pawlowski Laura , Peyvandi Shabnam
Published: June 2023

Introduction:
Racial inequities in congenital heart disease (CHD) are well documented. We examined the interplay between race, socioeconomic status (SES), and neonatal variables (prematurity and small for gestational age (SGA)) on 1-year mortality in infants with CHD.

Hypothesis:
SES and neonatal variables explain a significant part of observed racial disparities.

Methods:
Linked birth/death files from the Natality database for all liveborn neonates in the US were examined from 2014-2018. Infants with cyanotic CHD were identified. Non-Hispanic Black (NHB) infants were compared to non-Hispanic White (NHW) infants. The primary outcome was 1-year mortality. A composite measure of SES was created based on maternal education and insurance with a maximal level of 4 and a minimal level of 0 (least privileged). Other mediators included prematurity and SGA. A directed acyclic graph (Figure 1) was created a priori as a conceptual model. Additive structural equation modelling with bootstrapped confidence intervals was used to calculate the contribution of each pathway in Figure 1 to the primary outcome and percent mediated by SES, prematurity and SGA.

Results:
We identified 7,432 NHW and 1,452 NHB infants with cyanotic CHD. NHB race was associated with increased 1-year mortality (OR 1.40, 95% CI: 1.23-1.59) compared to NHW. Figure 1 shows the contribution of each pathway to one-year mortality. The effect of SES explained 35.9% (CI 22.0-67.3) of the mortality disparity between NHB and NHW race. The effect of SGA explained 16.5% (CI 8.8-30.2) and prematurity explained 12.0% (CI 5.4-26.1). The direct effect of NHB race was not significant (35.5%, CI -4.9 - 56.7).

Conclusions:
Less privileged SES and greater prematurity and SGA likely explain the 1-year mortality disparity in Black infants with cyanotic CHD. These findings identify targets for social intervention to decrease racial disparities in CHD outcomes.
Abstract 11590: Impact of Adverse Social and Behavioral Determinants of Health on In-Hospital Mortality Following an Acute Atherosclerotic Vascular Event at a Safety Net Community Hospital
Authors: Nyembo Philippe F , Rodin Holly , Shroff Gautam R
Published: June 2023

Introduction:
Safety net community hospitals (SNCH) care for patients with disproportionately high prevalence of adverse social and behavioral determinants of health (SBDH). We evaluated the impact of adverse SBDH on in-hospital mortality and 30-days readmission after a first atherosclerotic cardiovascular disease (ASCVD) event at a large urban SNCH.

Methods:
We performed a retrospective review of patients presenting with an ASCVD event (coronary heart disease, cerebrovascular disease, or peripheral artery disease) between 2015 and 2019. Adverse SBDH was defined as history of homelessness, mental illness, incarceration, or substance use disorder. We used logistic regression analysis to evaluate independent predictors of in-hospital mortality and 30-day readmission following ASCVD event.

Results:
A cohort of 1974 patients was identified, mean age 63.8 years with standard deviation (SD) of 14.5, patients with adverse SBDH were 8 years younger than those without any adverse SBDH (58.5 years,SD:12 vs. 66 years,SD:14.8; p<0.0001). Atleast one adverse SBDH was noted in 28% of the cohort. Using multivariable analysis, presence of SBDH was not an independent predictor of in-hospital mortality or 30-day readmission following ASCVD event. Age above 65 years tripled the likelihood of in-hospital mortality. Black race and age above 45 years were independent predictors of 30-days readmission. Patients on aspirin and antihypertensives prior to admission were less likely to die in the hospital (Table 1).

Conclusions:
In this cohort from a SCNH with 28% prevalence of adverse SBDH, the presence of any adverse SBDH did not impact in-hospital mortality or 30-day readmission. However, notably, patients with adverse SBDH presenting with an index ASCVD event were about a decade younger than those without adverse SBDH.
Abstract 11593: The Critical Role of Transthoracic Echocardiography in the Evaluation of Cardiogenic Shock and Takotsubo Cardiomyopathy
Authors: Spears Jenna , Al-Saiegh Yousif , olleik farah , Taoutel Roy , Steers John
Published: June 2023

Introduction:
Cardiogenic shock occurs in 10% of patients with takotsubo cardiomyopathy (TTC) as a result of severe systolic dysfunction, or left ventricular outflow tract (LVOT) obstruction.

Methods:
Case report and review of the literature.

Results:
A 62-year-old female with a history of hypertension and diabetes mellitus presented with lightheadedness, shortness of breath, and chest discomfort. She was hemodynamically unstable, tachycardic, and hypotensive (70/40 mmHg). Her EKG showed sinus tachycardia at 101 BPM with 1 mm ST depression in leads II, III, AVF; V3-V6. Chest radiograph revealed pulmonary edema. High-sensitive troponin was 146.7. She was intubated for respiratory distress and had rapidly increasing vasopressor requirements.

Emergent coronary angiography revealed nonobstructive coronary artery disease. A left ventriculogram revealed apical ballooning with an estimated ejection fraction of 25%, consistent with TTC. Transthoracic echocardiogram (TTE) showed severe mid and apical LV hypokinesis with basal hyperkinesis. Additionally, systolic anterior motion (SAM) of the mitral valve (MV) was noted, with a peak LVOT gradient of 7 mmHg. The patient improved clinically, and all support was weaned off. However, she later acutely developed recurrent respiratory distress and hypotension. Repeat TTE showed LVOT obstruction with a gradient of 40 mmHg due to increased basal hyperkinesis and SAM. The choice of vasopressor was switched from norepinephrine to phenylephrine to reduce the obstruction. She clinically improved and metoprolol succinate was added to reduce basal hypercontractility and improve left ventricular filling.

Conclusions:
Differentiating the mechanism of shock in TTC can easily be accomplished with TTE, and is essential to guiding treatment. The initial acute systolic dysfunction was effectively managed with norepinephrine, dopamine, and an intra-aortic balloon pump. She later developed LVOT obstruction as her systolic function improved. This was recognized with TTE and led to an appropriate change in vasopressor, as norepinephrine would have worsened the obstruction. This highlights the importance of early TTE in patients presenting with undifferentiated shock, especially when TTC is suspected.
Abstract 11610: Obesity and Metabolic Syndrome Among Heart Failure With Preserved Ejection Fraction Patients
Authors: Kallenbach Lee , Bae Jay P , Nelson David , Bonafede Mac , Lavelle Kevin , Hurt Karla , Murakami Masahiro
Published: June 2023

Introduction:
Recent data show a relative increase of HFpEF in heart failure. Additionally, an increase in prevalence of obesity and metabolic syndrome (MetS) in the population have been reported. Obesity and MetS differ across race, ethnicity, and sex. We sought to examine characteristics of patients with HFpEF by both obesity and MetS status to characterize differences in patient profiles for HFpEF.

Methods:
We examined data from the Practice Innovation and Clinical Excellence (PINNACLE) Registry® (American College of Cardiology and Veradigm) for HFpEF patients (LVEF ≥ 50%) and receiving care in a cardiologist clinic from 2016 thru 2019. Obesity is defined as BMI ≥ 30 kg/m
2
and MetS is approximated among patients with no history of myocardial infarction by presence of three of the four conditions (dyslipidemia, hypertension, obesity, and diabetes) at baseline.

Results:
Among 218,843 HFpEF patients, 56.7% had obesity, 50.4% had MetS, 34.8% had neither, and 41.8% had both. Obese patients were younger than non-obese (69.9 vs 74.9 years) and MetS patients were somewhat younger than non-MetS (71.7 vs 72.5 years). Over half of non-obese (62.7%) and non-MetS (53.8%) patients were 80+ years old. A higher proportion of women were obese than non-obese (57.8 vs 47.3%), while the proportion of women with and without MetS was similar (54.7 and 54.1%). Blacks have higher proportions of both obese and MetS than without (9.8 vs 5.2% and 9.6 vs 6.5%). Hispanics also have a higher proportion of MetS than without (4.9 vs 3.9%). MetS group exhibited a higher rate of all other cardiovascular comorbidities than the obesity group except for atrial fibrilation.

Conclusions:
In this large cohort of HFpEF patients in the ambulatory specialist care setting, nearly 2/3 of the HFpEF patients had obesity or MetS. MetS patients reflect an older more minority population with a higher proportion of comorbidities than obese patients.
Abstract 11616: Obstructive Sleep Apnea Disrupts Endothelial Cellular Cholesterol Trafficking
Authors: Gao Su , Shah Vikash Kumar , Emin Memet , Chang Audrey , Jelic Sanja
Published: June 2023

Introduction:
Obstructive sleep apnea (OSA), a highly prevalent disorder, triples cardiovascular risk. Our previous studies showed that intermittent hypoxia (IH), the hallmark of OSA, triggers endothelial cell (EC) inflammation by reducing protection against complement activity, which is cholesterol-dependent. We assessed whether IH promotes accumulation of cellular cholesterol in ECs in OSA patients and investigated the underlying mechanisms.

Methods:
We used ECs collected from OSA patients and cultured human umbilical vein ECs (HUVECs) exposed to IH (alternating 30 min 21% O
2
for normoxia/30 min 2% O
2
for hypoxia for 8 h).

Results:
Levels of free, cellular cholesterol were increased and the presence of lipid droplets was reduced in ECs from OSA patients compared with OSA-free controls as well as in HUVECs exposed to IH compared with normoxia. Cholesterol uptake and synthesis were similar in normoxia and IH. In contrast, co-localization of free cholesterol and late endosome/lysosome (LE/LY) was increased in IH compared with normoxia, suggesting impaired trafficking of free cholesterol from LE/LY to endoplasmic reticulum (ER) in IH. Immunoglobulin binding protein (BiP), a marker of ER stress, was upregulated in ECs of OSA patients compared with controls. IH-induced ER stress reduced interaction between LE/LY-bound oxysterol binding protein-related protein-1L (ORP1L) and ER-bound VAMP-associated protein-B (VAPB), which is required for cholesterol trafficking from LE/LY to ER. After screening ER-associated degradation machinery components for potential binding to VAPB in IH, we identified Derlin1 as a ligand that binds increasingly to VAPB in IH thereby potentially reducing interaction between ORP1L and VAPB. In OSA patients, ORP1L-VAPB interaction was reduced whereas Derlin1-VAPB was increased and positive airway pressure, a standard therapy for OSA, reversed these changes.

Conclusions:
IH induces ER stress that disrupts cholesterol trafficking from LE/LY to ER leading to accumulation of free cholesterol in ECs, which underlies impaired endothelial protection against complement and endothelial inflammation that may increase cardiovascular risk in OSA.
Abstract 11617: Chronic Spinal Cord Stimulation Mitigates Cardiac Sympathoexcitation and Reduces Ventricular Arrhythmias Induced by Myocardial Infarction
Authors: Kuwabara Yuki , Salavatian Siamak , Howard-Quijano Kimberly , Mahajan Aman
Published: June 2023

Introduction:
Spinal cord stimulation (SCS) is effective neuromodulation therapy for pain, but little is known about the effectiveness of SCS for arrhythmia prevention in chronic myocardial infarction (MI).

Hypothesis:
Chronic SCS reduces MI-induced cardiac sympathoexcitation and reduces ventricular arrhythmias.

Methods:
Yorkshire pigs were randomized to chronic left circumflex coronary artery MI alone (n=11) or MI + chronic SCS (n=9). Epidural SCS lead was placed percutaneously T1-T4 of the spinal cord and reactive SCS was performed at 10 kHz, 0.03ms, and 2.5mA after MI. Holter ECG was recorded for heart rate variability (HRV) analysis, performed throughout 4-5 weeks post-MI. To create acute stress in chronic MI, epicardial extraventricular programmed stimulus (S1/S2 pacing), and acute left anterior descending coronary artery (LAD) ischemia(1h)+reperfusion(2h) (I/R) injury were conducted during terminal experiment. SCS was continued throughout terminal experiment. Cardiac electrophysiological data (activation recovery interval (ARI) and dispersion of repolarization (DOR)), as well as ventricular arrhythmia quantification were measured by placing a 56-electrode mesh sock over the heart . Data is shown as mean±SEM.

Results:
1 week after MI, 30min HRV showed a higher high-frequency band and lower very-low and low-frequency band with SCS (%HF: MI 25±4 vs SCS 51±4, p=0.0028. %VLF: 50±4 vs 30±3, p=0.0015. %LF: 22±2 vs 14±2, p=0.047). In the terminal experiment, SCS reduced the maximum slope (Smax) of the electrical restitution curve described by S1/S2 pacing (Smax: MI 0.6±0.03 vs SCS 0.4±0.05, p=0.023). After acute LAD ischemia, SCS reduced global %ARI change (MI -19±3% vs SCS -11±1%, p=0.019), specifically in the ischemic region (MI -31±4% vs SCS -16±3%, p=0.008), and global %DOR (MI 1513±288% vs SCS 595±144%, p=0.011). Chronic SCS also reduced ventricular tachycardia and ventricular fibrillation during acute I/R (MI 15±3 vs SCS 5±0.8, p=0.014).

Conclusions:
Reactive SCS therapy mitigates cardiac autonomic imbalance in chronic MI and protects from new acute ischemia induced cardiac sympathoexcitation and ventricular arrhythmias.
Abstract 11627: Genetic Testing for Hereditary Amyloid Transthyretin Amyloidosis: Insights From the Compass Program
Authors: Bhatt Kunal , Delgado Diego H , Khella Sami , Towne Meghan C , Kaeser Gwendolyn E , Sanjurjo Victoria , Shah Keyur B
Published: June 2023

Introduction:
Hereditary amyloid transthyretin (hATTR, or ATTRv [variant]) amyloidosis is a progressive and fatal disease caused by alterations in the transthyretin (
TTR
) gene that result in the deposition of misfolded protein throughout the body, leading to multisystem dysfunction. The p.V142I and p.T80A pathogenic alterations typically manifest with a cardiac phenotype, and early diagnosis is crucial to achieving optimal patient outcomes. The hATTR Compass Program offers confidential genetic testing to patients suspected of having hATTR in the United States, Canada, and Puerto Rico.

Methods:
Patients were referred to Compass for genetic testing using a
TTR
single-gene analysis, a cardiovascular-focused 92-gene panel, or a neuropathy-focused 81-gene panel. All patient demographics were self-reported. This report analyzes patients with
TTR
alterations.

Results:
A total of 22,801 patients were referred for genetic testing; 1469 (6%) patients were positive for
TTR
. Of those, 1237 (84%) had the p.V142I alteration and 73 (5%) had the p.T80A alteration. Patients with p.V142I were predominantly Black (81%), while patients with p.T80A were predominantly White (86%). Most p.V142I patients were male (60%), while 48% of p.T80A patients were male. The average age at testing was earlier in patients with p.T80A (56 y) compared with p.V142I (67 y). The majority of p.T80A patients reported a family history of ATTR (64%), contrasting with only 23% of p.V142I patients. In patients with p.V142I and p.T80A who reported symptoms (1049 vs 42, respectively), most reported heart disease (90% vs 71%). Other symptoms included bilateral carpel tunnel syndrome (24% vs 31%), renal issues (22% vs 12%), and gastrointestinal issues (9% vs 31%). Patients with p.T80A reported a higher incidence of sensory (52%), motor (31%), and autonomic (29%) dysfunction compared with patients with p.V142I (31%, 18%, and 21%, respectively).

Conclusions:
Patients with p.V142I were mostly Black and were less likely to have a known family history of hATTR. Both p.V142I and p.T80A patients presented with mixed symptoms, including heart disease and polyneuropathies. Genetic testing may be an efficient path toward early diagnosis and treatment for this progressive and fatal disease.
Abstract 11634: Fatty Acid Length Dictates Association of Sphingomyelins With Sudden Cardiac Death
Authors: Bockus Lee , Jensen Paul , Fretts Amanda M , Hoofnagle Andy , Sitlani Colleen , Siscovick David , Psaty Bruce M , Sotoodehnia Nona , Lemaitre Rozenn N
Published: June 2023

Background:
Sudden cardiac death (SCD) is a leading cause of mortality worldwide and is precipitated primarily by ventricular tachyarrhythmias related to coronary artery disease. Sphingolipids, composed of ceramides and sphingomyelins, may influence the pathophysiology and risk of SCD through multiple biological activities. Whether the length of the fatty acid conjugated to the sphingolipid species is associated with SCD risk is not known.

Methods and Results:
Among 4612 Cardiovascular Health Study participants, we identified 215 patients who experienced SCD over a median follow up of 10.2 years. We examined 8 sphingolipids: ceramide and sphingomyelin species containing palmitic acid and species containing, respectively, the very-long-chain saturated fatty acids (VLSFA) arachidic, behenic, and lignoceric acids. In adjusted Cox regression analyses, ceramides and sphingomyelins with palmitic acid were associated with increased SCD risk per standard deviation log difference (ceramide with palmitic acid: hazard ratio 1.34, 95% CI 1.12-1.59; sphingomyelin with palmitic acid: hazard ratio 1.37, 95% CI 1.12-1.67). In contrast, one sphingomyelin with a VLSFA trended towards an association with reduced SCD risk (sphingomyelin with arachidic acid: hazard ratio 0.83, 95% CI 0.71-0.98). Associations were weakened when adjusted for C-reactive protein (CRP), B-type natriuretic peptide, and troponin-T, but did not differ significantly by age, sex, race, body-mass index, or history of coronary heart disease. In comparison, ceramide with palmitic acid was associated with higher risk of nonfatal myocardial infarction, and ceramide with the VLSFA lignoceric acid trended towards lower risk.

Conclusions:
Our results suggest associations between sphingolipid species and SCD, differing by the length of the acylated saturated fatty acid. Palmitic acid-containing sphingolipids were strongly associated with increased SCD risk, whereas VLSFA-containing sphingomyelins trended toward reduced SCD risk. The study indicates that plasma sphingolipids may influence the risk of SCD, independent of traditional cardiovascular risk factors. Our findings may provide further insight into the pathogenesis of SCD and enhance risk stratification tools.