bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16915: Extracorporeal Membrane Oxygenation for Pulmonary Embolism With Acute Right Ventricular Failure and Shock: National Trends of Use, Demographics and In-Patient Mortality in the United States 2011-2014
Authors: Arora Ayush , Tsangaris Adamantios , Amin Akhtar , Satya Kumar
Published: April 2024

Background:
Extracorporeal membrane oxygenation (ECMO) is an emerging option for cardio-pulmonary support for patients with massive pulmonary emboli (PE) as a bridge to definitive treatments. Goal of this study is to assess the national trends of use, demographics and in-patient mortality of patients managed with ECMO for PE associated with acute right ventricular failure and shock.

Methods:
The National Inpatient Sample database was queried for patients above 18 years of age hospitalized between 2011-2014 with pulmonary emboli (ICD diagnoses codes 415.1, 415.11, 415.19). Patients with acute right ventricular failure and shock with hemodynamic instability were identified (ICD diagnoses codes 415.0, 785.59, 785.51, 785.50). Patients treated with ECMO were identified using the procedure code 39.65. SPSS version 24 was used for statistical analysis.

Results:
During the study period, there were 1,262,542 admissions with pulmonary emboli, out of which 32,978 had acute right ventricular failure and shock. ECMO was used in 450 patients and that showed an increasing trend over the years (figure 1), with an in-patient mortality rate of 59.2%. Mean length of stay was 23 days. More than 90% of these patients were managed in large urban teaching hospitals with bed-size more than 500. Around half (43%) of these were in the Southern US hospitals. Factors associated with higher mortality were male sex (68.8%), age >80 years (100%), Hispanic race (65%), lack of insurance (71.4%) and low socio-economic strata (income quartile 1st, 74.4%), p<0.05.

Conclusion:
Use of ECMO for cardio-pulmonary support in patients hospitalized for PE with acute right ventricular failure and shock is increasing over the years. Among these patients, male sex, age >80 years, Hispanic race, lack of insurance and lower socio-economic strata are associated with higher mortality.
Abstract 16925: KLF and AP1 Having Opposing Roles in Regulating Chromatin Accessibility and the Endothelial Enhancer Landscape Under Laminar vs. Disturbed Shear Stress
Authors: Moonen Jan-Renier , Chappell James , Dan Li , Shi Minyi , Cao Aiqin , Taylor Shalina , Zhao Zhixin , Wang Lingli , Snyder Michael P , Rabinovitch Marlene
Published: April 2024

Background:
Laminar shear stress (LSS) is associated with a vasculoprotective endothelial phenotype, while exposure to disturbed shear stress (DSS) is linked to endothelial dysfunction and vascular disease. Epigenetic changes in chromatin accessibility and enhancer dynamics are important regulators of gene expression. We hypothesized that LSS and DSS induce distinct transcription factors that recruit chromatin remodelers to change the chromatin landscape, making it permissive for either protective or disease-related gene expression profiles.

Methods & Results:
Human pulmonary arterial endothelial cells were exposed to LSS (15 dyne/cm2) or DSS (±3 dyne/cm2, 0.8 Hz; and static) for 24h and analyzed by ATAC-Seq and RNA-Seq. Exposure to LSS resulted in increased chromatin accessibility, predominantly in regions within 100 kb of transcription start sites. These changes correlated with induction of protective, and suppression of disease-related genes. Many differentially accessible regions were also differentially marked by H3K27ac and H3K4me1 enhancer marks, as identified by ChIP-Seq. Motif analyses found enrichment for KLF binding sites in enhancers that are open under LSS vs. enrichment for AP1 at enhancers that are open under DSS. ChIP-Seq for KLF and AP1 confirmed differential binding at those sites. Gain-and-loss of function studies using a constitutive active mutant of MEK5, which induces KLF akin to LSS, and RNAi for KLF and AP1 confirmed that these factors were required to differentially mediate accessibility changes under LSS and DSS. We then used IP-MS to identify the chromatin remodelers recruited by KLF, and uncovered several components of the SWI/SNF nucleosome remodeling complex. Co-IP assays confirmed interaction of SWI/SNF with KLF under LSS. This was further documented by in situ proximity ligation assays. Under conditions of DSS we observed nuclear translocation of AP1 member ATF2 that interacts with c-Jun, which is enriched at enhancers that are open under DSS.

Conclusions:
KLF and AP1 differentially regulate the endothelial enhancer landscape under laminar vs. disturbed shear stress, which culminates in protective or disease-related gene expression profiles.
Abstract 16932: Glucagon-Like Peptide 1 Receptor Agonist Mitigates Postinfarction Adverse Left Ventricular (LV) Remodeling in Mice; a Mechanism Linked to Mitophagy and the Restoration of Cardiac Fatty Acid Oxidation
Authors: Andres Allen M , Germano Juliana , Huang Chengqun , Sin Jon , Song Yang , Tucker Kyle C , Gottlieb Roberta A , Mentzer Robert M
Published: April 2024

Glucagon-like peptide 1 receptor agonist (GLP1Ra) and its variants have been shown to protect against cardiac ischemic injury. Less is known about their effects on adverse post-MI LV remodeling. Based on our observation that GLP1Ra stimulated mitophagy in H9C2 cardiac cells, we evaluated its effects on post-MI remodeling. Mice underwent permanent coronary artery ligation (PCAL), ensuring remodeling would be independent of changes in infarct size. Vehicle or GLP1Ra (Sigma) were administered i.p. 2h

after the infarct

and then every other day for a total of 6 doses. LV remodeling was assessed 30 days post-MI via echo. Histology was used to examine immune cell infiltration 7 days post-MI (early phase) via hematoxylin and eosin staining, and fibrosis by Masson’s trichrome after 30 days (late phase). GLP1Ra-treated mice exhibited a marked reduction in immune cell infiltration (
A
), and fibrosis (
B
). This corresponded to a significant improvement in ejection fraction (EF) and fractional shortening (FS) (
C
), although not to the levels of sham-operated mice (EF 60% and FS 30%, data not shown). We assessed the importance of GLP1Ra-induced mitophagy in Parkin KO (PKO) mice. GLP1Ra failed to attenuate adverse remodeling (
D and E
) and immune cell infiltration (
F
) in PKO mice implicating the importance of mitophagy as an underlying mechanism. We next determined the effect of GLP1Ra on the activation state of the pyruvate dehydrogenase complex (PDC), which governs substrate utilization. Ischemically injured hearts shift fuel use towards carbohydrate oxidation, which we confirmed in our PCAL model via decreased phosphorylation of the PDC. Post-MI administration of GLP1Ra promoted PDC phosphorylation and thereby restored fatty acid utilization during the early phase of remodeling (
G and H
). These findings suggest that alterations in cardiac metabolic poise after ischemic injury play a role in adverse remodeling and that stimulation of mitochondrial turnover influences this process.
Abstract 16949: Conventional Bystander CPR is Associated With Higher Neurologically Favorable Survival in Children Compared to Compression Only CPR Following Pediatric Out of Hospital Cardiac Arrest
Authors: Naim Maryam Y , Griffis Heather , Berg Robert A , Bradley Richard N , Burke Rita V , Markenson David , McNally Bryan F , Nadkarni Vinay M , Song Lihai , Vellano Kimberly , Rossano Joseph W
Published: April 2024

Introduction:
There are conflicting data regarding the benefit of conventional bystander CPR (BCPR) compared to compression only BCPR (CO-BCPR) for children following out of hospital cardiac arrest (OHCA).

Hypothesis:
Conventional BCPR is associated with improved outcome compared to CO-BCPR in infants, children and adolescents following OHCA.

Methods:
An analysis of the Cardiac Arrest Registry to Enhance Survival was conducted. Inclusion criteria were age ≤ 18 years and non-traumatic OHCA from 2013 through 2017. The primary outcome was neurologically favorable survival (cerebral performance category score of 1 or 2). Age groups included infants (≤1 year), children (2-11 years), and adolescents (≥12 years).

Results:
Of 6249 cardiac arrests, 1191 received conventional BCPR, 1386 received CO-BCPR, and 3672 received no BCPR. The highest neurologically favorable survival was associated with conventional BCPR (adjusted proportion12.5%, OR 2.5, 95% CI 1.9, 3.2) for the overall cohort compared to CO-BCPR (9%, OR 1.6, 95% CI 1.2, 2.0) and no BCPR (6.4%). Conventional BCPR was significantly associated with improved neurologically favorable survival vs. no BCPR in the overall cohort and in all age groups (infants 9.4% vs. 5.4%, children 17.9% vs. 6.2%, adolescents 14% vs. 8,1%, p-value (for all) <0.001). Conventional BCPR was also significantly associated with improved neurologically favorable survival vs. CO-BCPR in the overall cohort and for infants (9.4% vs. 6.1%, p=0.02). CO-BCPR was significantly associated with improved neurologically favorable survival compared to no BCPR in the overall cohort and in children (13.5% vs. 6.2%, p<0.001), but not in infants or adolescents.

Conclusion:
Conventional BCPR was associated with higher neurologically favorable survival compared to no BCPR in all children and compared to CO-BCPR in most age groups. These results support current AHA/ILCOR recommendations for the provision of conventional BCPR in pediatric OHCA.
Abstract 16982: Adenylyl Cyclase Isoform 1 Plays a Critical Role in Beta-Adrenergic Response of Pacemaking Cells in Sinoatrial Node
Authors: Ren Lu , Thai Phung N , Timofeyev Valeriy , Ledford Hannah A , Sirish Padmini , Moreno Moreno Claudia , Ngo Richard Q , Fernando Santana Luis , Kotlikoff Michael I , Xiang Yang K , Yarov-Yarovoy Vladimir , Zhang Xiaodong , Chiamvimonvat Nipavan
Published: April 2024

Introduction:
Sinoatrial node (SAN), the primary pacemaker region of the heart, is the main determinant of heart rate, which is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR signaling pathway. There are 10 known AC isoforms but it is unclear which AC isoforms are predominant in the SAN. Furthermore, their functional roles in regulating the pacemaking activity of the heart is not well understood.

Hypothesis:
We hypothesize that distinct AC isoforms are preferentially expressed in SAN and serve specialized function compared to atrial and ventricular myocytes.

Methods:
Regional distribution of AC isoforms in the heart was determined using single-cell RT-PCR and single molecule fluorescence in situ hybridization. Transgenic mice expressing GCaMP8 under HCN4 promoter was used to identify SAN cells. To determine the role of AC isoforms in the SAN, CRISPR/Cas9 gene editing was used to generate SAN specific knockout (KO) mice. Electrocardiogram was performed to determine heart rate during basal condition and after β-AR stimulation with isoproterenol (ISO). Analyses of Ca
2+
and pacemaking currents as well as local Ca
2+
release were performed in single isolated SAN cells from the KO mice with and without β-AR stimulation.

Results:
Single-cell RT-PCR showed that in the SAN, AC
I
is the most abundant isoform, followed by AC
VI
, AC
VII
, AC
III
and AC
IV
. In contrast, AC
VI
was the most abundant isoform in both atria and ventricles. CRISPR/Cas9-mediated gene silencing of AC
I
resulted in a decrease in heart rate with blunted response to ISO (Figure 1). In contrast, AC
V
/AC
VI
double KO mice exhibited similar heart rate responses to ISO compared to WT mice, suggesting that AC
V
/AC
VI
isoforms do not play critical roles in controlling the SAN firing frequency.

Conclusions:
Our study suggests AC
I
plays a critical role in β-AR response of pacemaking cells in SAN and may offer unique therapeutic opportunities to directly modify pacemaking cells without interfering with ventricular myocytes.
Abstract 17001: Nebulette Knock-Out in Mice Leads to Dilated Cardiomyopathy
Authors: Turdi Subat , Sullivan Ryan D , Towbin Jeffrey A
Published: April 2024

Introduction:
Cardiomyopathy is a serious heart condition that can lead to heart failure. Nebulette is a cardiac-specific Z-disk protein which plays a crucial role in mechanosensing and force generation in the heart. Previous studies have shown that nebulette mutations are associated with various cardiomyopathies including hypertrophic, left ventricular noncompaction and dilated cardiomyopathy. However, the molecular mechanisms by which nebulette affects the cardiac structure and function are not well-understood.

Hypothesis:
In this study, we tested whether decrease in nebulette causes cardiac remodeling, dysfunction and dilated cardiomyopathy
in vivo.

Methods:
We generated a novel nebulette knockout (KO, excision of exon 3) mice using the Cre/loxP technique. Mice were characterized prior to being subjected to serial echocardiography and electrocardiogram (ECG) at 6 weeks, 3 months, 6 months and one year of age. A separate cohort of mice were used for histopathological and molecular studies.

Results:
KO mice were born following Mendelian laws. Western blot and qPCR data revealed significant decrease in nebulette expression in KO mouse hearts compared to heterozygous (Het) and WT mice. Confocal microscopy further elicited diminished nebulette expression and perturbed distribution in myocardial sections as well as isolated cardiomyocytes from KO mice. Echocardiography showed a deterioration of cardiac function in KO mice starting from 6 weeks of age to one year of age, which were characterized by reduced fractional shortening and MV E/A, increased LV diastolic dimension as compared with age-matched WT mice. KO mice showed tachycardia and lower QRS voltage at one year of age compared to WT and Het mice. KO hearts revealed increased fibrosis, sarcomere disorganization, enlarged t-tubules and less apparent M-lines. Western blot demonstrated reduced cardiac TnT and increased TnI levels in the KO mice whereas desmin, actin and cardiac ankyrin repeat protein (CARP) remained comparable between the genotypes.

Conclusions:
Taken together, these data provide evidence for the critical role of nebulette in maintaining cardiac structure and function. Further data that provides mechanistic insight will be presented.
Abstract 17002: It’s All in the Tissue: A Rare Case of Acute Cardiogenic Shock
Authors: Narang Nikhil , Chung Bow , Nguyen Ann , Imamura Teruhiko , Kalantari Sara , Smith Bryan A , Kim Gene H , Raikhelkar Jayant , Sarswat Nitasha , Song Tae H , Ota Takeyoshi , Onsager David , Jeevanandam Valluvan , Sayer Gabriel T , Uriel Nir
Published: April 2024

A 53-year-old female with a history of hypothyroidism presented with a 2-week history of dyspnea and abdominal pain. Exam revealed a heart rate of 120 bpm, blood pressure of 87/69 mmHg, elevated JVP, and a 3/6 holosystolic murmur. EKG showed 2 mm ST-segment elevations in V1-V3 and ST-segment depressions in lateral limb leads. Labs showed transaminitis, elevated troponin-T, lactic acid and leukocytosis. An echocardiogram revealed severely reduced global biventricular dysfunction with a normal chamber size. Differential included acute coronary syndrome and myocarditis, with unknown subtype.

Coronary angiogram revealed normal coronaries, while right heart catheterization found elevated biventricular pressures/low flow (RA 19 mmHg, RV 33/15 mmHg, PAP 32/19/25 mmHg, PCWP 25 mmHg, Fick CI 1.5 L/min/m
2
). Endomyocardial biopsy was performed to assess acute cardiogenic shock. Intra-aortic balloon pump was placed for stabilization, but she developed ventricular arrhythmias and urgently underwent implantation of CentriMag biventricular assist devices. The biopsy revealed a diffuse lymphocytic infiltrate and multinucleated giant cells without granulomas consistent with giant cell myocarditis (GCM) (Fig 1). A combination of high-dose prednisone, Tacrolimus and IVIG was initiated. The patients’ condition improved and 12 days following BiVAD implantation the patient had “turn-down” study of the BiVADs (simultaneous echocardiographic and hemodynamics step wise reduction in speed which showed evidence of myocardial recovery). The devices were explanted and the patient was discharged on oral medical therapy plus immunosuppression.

The case discusses the (1) indication for early endomyocardial biopsy in setting of cardiogenic shock with unknown etiology (2) medical therapy for GCM include steroids/Tacrolimus (3) acute mechanical support in the setting of myocarditis complicated by cardiogenic shock and (4) turn down study to assess myocardial recovery.
Abstract 17005: Racial Differences in Mortality in Patients With Severe Aortic Stenosis After Aortic Valve Replacement
Authors: White Solaru Khendi T , Popovic Zoran , Kalahasti Vidyasagar , Roselli Eric , Barzilai Benico
Published: April 2024

Introduction:
Aortic valve replacement (AVR) improves survival in patients with aortic stenosis (AS) or congenital bicuspid AV (BAV). To the authors’ knowledge, there are no studies that have examined racial differences in mortality after AVR for patients with severe AS or BAV. It is unknown whether AA patients undergoing AVR have worse outcomes and if they are impacted by confounding variables such as socioeconomic status.

Hypothesis:
We sought to identify clinical characteristics in African Americans (AAs) and Whites who had AVR for severe AS. We hypothesized that there would be significantly higher mortality in AAs that would diminish after adjusting for differences in socioeconomic status and prevalence of other clinical characteristics such as hypertension and LV hypertrophy.

Methods:
Retrospective analysis was performed on 10,299 AA or Caucasian patients with severe AS or BAV treated at Cleveland Clinic with primary AVR from 1/1/2000 to 1/1/2017. Short- and long-term survival was assessed non-parametrically by the Kaplan-Meier method in both the unadjusted and matched groups. We used a propensity score strategy to match the two groups on a multitude of clinical and socioeconomic variables which yielded 201 matched pairs.

Results:
Median follow-up for death was 3.86 years. AAs had significantly higher short- and long- term mortality in the unadjusted analysis (p<0.001). After rigorous propensity matching, there was no significant differences between the groups (p=0.19). AAs were significantly more likely to have hypertension, diabetes, renal failure, CVA, and LVH. The biggest contributors to mortality in AAs according to our saturated model (C-statistic=0.93) were unemployment rate, poverty level, posterior wall thickness, degree of heart failure, LV mass, diabetes, preoperative creatinine, and hypertension, respectively.

Conclusions:
Our study is the largest of its kind and unique in its finding that African Americans have significantly higher mortality after AVR as compared to Caucasians but no significant differences after propensity matching. This suggests that the differences in mortality outcomes are largely driven by differences in socioeconomic status.
Abstract 17006: A Machine Learning Approach to Identify Predictors of Mortality in Patients With Atherosclerotic Cardiovascular Disease
Authors: Dikilitas Ozan , He Baosheng , Kullo Iftikhar
Published: April 2024

Introduction:
We investigated the predictive power of a machine learning (ML) algorithm for 5-year mortality in patients with atherosclerotic cardiovascular disease (ASCVD). Candidate features included clinical variables from the electronic health record (EHR) as well as self-reported health and lifestyle data.

Methods:
The study cohort included 4,689 patients (66±11 years, 62% male) with ASCVD enrolled in the Vascular Disease Biorepository, which recruits patients referred to noninvasive vascular evaluation at Mayo Clinic, Rochester, MN. Clinical variables including comorbidities, lab measurements, and medication use were obtained from the EHR using validated electronic phenotyping algorithms. Information regarding social habits, physical activity levels, and personal health was obtained from a survey filled by the participants. Mortality was ascertained from the national death index. Clinical variables (n=52) and self-reported variables related to health and lifestyle habits (n=48) were added as individual features to reinforcement learning trees (RLT), a sparse decision tree algorithm, to construct the prediction model. We assessed the impact of each feature on prediction accuracy by applying feature selection and computing variable importance (VI).

Results:
Features with trivial VI that made no contribution to prediction were excluded. A model with 15 features had an area under the ROC curve (AUC) of 0.82 [95% CI 0.79 - 0.83] in the test set. Among the top 10 predictors of 5-year mortality, 6 were self-reported health variables
(Table)
, including outlook on personal health, limitations on routine daily activities, and physical activity levels.

Conclusions:
A ML approach had robust discrimination (AUC 0.82) in predicting 5-year mortality in patients with ASCVD. Self-reported health variables were among the top predictive features in the final model.
Abstract 11900: Quinidine as Salvage Therapy in Recurrent Monomorphic Ventricular Tachycardia
Authors: Larson John D , Deshmukh Amrish , Ghannam Michael , Cunnane Ryan , Ghanbari Hamid , Latchamsetty Rakesh , Crawford Thomas , Jongnarangsin Krit , Oral Hakan , Morady Fred , Bogun Frank , Liang Jackson
Published: April 2024

Introduction:
Quinidine is an effective therapy for a subset of polymorphic ventricular tachycardias and ventricular fibrillation (VF), however the efficacy of quinidine on scar related monomorphic ventricular tachycardia (MMVT) is unclear.

Hypothesis:
We sought to assess the efficacy and adverse effects of quinidine in scar related MMVT.

Methods:
All patients with MMVT treated with quinidine from 2009-2020 at a single VT referral center were reviewed.

Results:
A total of 22 patients with MMVT and structural heart disease (age 66.7 ± 10.9, 20 males, 15 with ischemic cardiomyopathy, mean LVEF 22.2 ± 12.3%, 9 with left ventricular assist device (LVAD)) were treated with quinidine (14 patients on Gluconate formulation average dose 996mg±321, 8 patients on Sulfate formulation with average dose 1062mg±588). Quinidine was used in combination with other antiarrhythmics (AAD) in 18 (13 also on amiodarone). All patients previously failed >1 AAD (Amiodarone 100%, mexiletine 73%, sotalol 32%, other 32%) and 8 had prior ablations (median of 1.5). Quinidine was initiated in the setting of VT storm despite other AADs (6), inability to tolerate other AADs (4), or recurrent VT despite prior therapies (12). Ventricular arrhythmias requiring ICD or external shock occurred despite quinidine in 13 (59%) patients at a median of 26 (4-240) days after quinidine initiation. In patients with recurrent MMVT, VT cycle length increased from 359ms to 434ms (p=0.02). Treatment with quinidine was associated with an increase in QTc from 527ms (413-619) to 554ms (425-725) (p=0.004). Only 6 patients remained on quinidine at 1 year with recurrence of ventricular arrhythmias in all. Of the 6 patients on long term quinidine therapy, 3 patients had no shocks but did receive successful ATP within the first year. The following adverse effects were seen: GI side effects (6), QT prolongation (2), rash (1), thrombocytopenia (1), neurologic side effects (1). One patient discontinued due to cost.

Conclusions:
Quinidine therapy has limited tolerability and efficacy when used in the management of amiodarone-refractory scar related MMVT. When possible, more effective therapies should be offered in patients with VT refractory to standard pharmacologic therapies.
Abstract 11919: Igg1 Phosphorylcholine Diminishes Murine Atherosclerosis and Ameliorates Plaque Stability via Reduced Intraplaque Angiogenesis and Hemorrhage
Authors: de Vries Margreet R , Baganha Fabiana , Peters Erna , Pettersson Knut , Quax Paul H
Published: April 2024

Introduction:
Phosphorylcholine (PC), one of the main oxLDL epitopes, is an important pro-inflammatory damage associated molecular pattern. Epidemiologic data show that natural anti-PC IgM protect against cardiovascular disease. Within atherosclerotic lesions, inflammation and angiogenesis are linked via VEGFA secreting CD163
+
macrophages. PC antibodies are recognized for their anti-inflammatory properties, the effect of PC antibodies on intraplaque angiogenesis (IPA) and intraplaque hemorrhage (IPH) is yet unknown.

Hypothesis:
Newly developed IgG1 PC antibody (PCmAb) inhibits lesion development via IPA and IPH reduction in murine vein graft atherosclerosis.

Methods:
Hypercholesterolemic male ApoE3*Leiden mice received a (donor) caval vein interposition in the carotid artery and weekly ip injections of (5mg/kg) PCmAb (n=11) or vehicle (n=12) until sacrifice at day 28. Vein graft morphometry and lesion composition including IPA and IPH were evaluated via immunohistochemistry. In vitro PCmAb effects were investigated in Hemoglobin (Hb):Haptoglobin(Hp)-cultured THP-1 macrophages and HUVECs.

Results:
PCmAb significantly decreased vein graft media area (13%), intima lesion (25%), and increased lumen area with 53% compared to vehicle. PCmAb improved lesion stability by increasing collagen content (18%) and decreased macrophages presence (31%). VCAM-1 and ICAM-1 expression in the vessel wall were also reduced (29%, 36%). PCmAb resulted in 23% decreased CD163
+
macrophages content in vein grafts whereas CD163 expression was reduced in Hb:Hp stimulated macrophages. PCmAb significantly reduced neovessel density (34%) and significant reduced EC proliferation and migration with and without oxLDL stimulation. Moreover, PCmAb enhanced maturation of intraplaque angiogenic vessels by increasing neovessel pericyte coverage
in vivo
(31%). Together, this resulted in a 62%reduction of IPH.

Conclusions:
PCmAb effectively inhibits murine atherosclerotic lesion formation. PCmAb reduces IPA and IPH by decreased neovessel density and macrophages influx via reduced expression of VCAM-1 and ICAM-1, and increased neovessel maturation in vein graft atherosclerosis. PCmAb holds promise as a new therapeutic approach for plaque stability.
Abstract 11929: PAI-1 is Cardioprotective in Human Inflammatory Cardiomyopathy
Authors: Baumeier Christian , Escher Felicitas , Aleshcheva Ganna , Pietsch Heiko , Schultheiss Heinz-Peter
Published: April 2024

Introduction:
Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing fibrosis through TGF-β and plasminogen mediated pathways. Moreover, PAI-1 is suggested to be involved in the recruitment and polarization of M2 macrophages.

Hypothesis:
Elevated myocardial PAI-1 expression protects from fibrosis and acute inflammatory response.

Methods:
Endomyocardial biopsies (EMBs) of patients with dilated cardiomyopathy (DCM, n=27) and inflammatory dilated cardiomyopathy (DCMi, n=149) were retrospectively analyzed for PAI-1 expression, markers of fibrosis and M1/M2 macrophage polarization.

Results:
Patients with high-grade myocardial inflammation (DCMi-high, CD3
+
lymphocytes > 30 cells/mm
2
) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3
+
lymphocytes = 14 - 30 cells/mm
2
) (15.5 ± 0.4 %
vs.
1.0 ± 0.1 % and 4.0 ± 0.1 %,
p
≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of tissue fibrosis, accompanied by decreased levels of TGF-β and a reduced number of cardiac myofibroblasts. In addition, elevation of PAI-1 led to a shift from M1 to M2 macrophages.

Conclusions:
Our findings give evidence that increased expression of PAI-1 in DCMi patients suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies.
Abstract 11942: Contemporary Management and Outcomes of Superior Vena Cava Syndrome in the United States: Insights From the Nationwide Readmissions Database
Authors: Zhao Matthew , Shafi Irfan , Azizi Abdul H , Lakhter Vladimir , Bashir Riyaz
Published: April 2024

Introduction:
The outcomes of superior vena cava (SVC) syndrome in contemporary clinical practice are not well known. We aimed to evaluate in-hospital mortality and unplanned readmission rates in these patients.

Methods:
We used the United States Nationwide Readmissions Database from January 2016 to December 2018 to identify patients hospitalized for SVC syndrome. We used ICD 10 codes to identify various treatments utilized in this cohort of patients. We assessed the in-hospital mortality and its independent predictors by using a multivariate logistic regression model. We also evaluated for 30-day unplanned readmission rates in these patients.

Results:
A total of 554 hospitalizations for SVC syndrome were identified. The most common treatment modalities included endovascular stenting (n=122; 22.0%), catheter-directed thrombolysis (n=54; 9.7%), and percutaneous thrombectomy (n=46; 8.3%). A total of 388 patients (70.0%) were managed non-invasively for their SVC syndrome. Hospitalized patients with SVC syndrome rarely received radiotherapy or open thrombectomy. In-hospital mortality was 3.6% (n=20), and its independent predictors included pulmonary embolism (OR 3.44; 95% CI 1.21-9.79; p=0.020), malignancy (OR 3.71; 95% CI 1.39-9.92; p=0.009), sepsis (OR 9.17; 95% CI 2.22-37.81; p=0.002), and pacemaker placement (OR 70.40; 95% CI 3.94-1257.17; p=0.004). Among patients who survived initial hospitalization and initial discharge (n=485; 87.5%), the unplanned 30-day readmission rate was 22.1% (n=107).

Conclusions:
In this nationwide observational study endovascular stenting was the most common treatment modality used to treat patients with SVC syndrome. These patients have high readmission rates as well as high in-hospital mortality. The major predictors of in-hospital mortality include pulmonary embolism, malignancy, sepsis, and pacemaker placement.
Abstract 11955: Heart Disease as a Risk Factor for Dementia Has Higher Association in Women Than in Men
Authors: Zhu Dongshan , Hao wenting , Fu Chunying
Published: April 2024

Introduction:
Cardiovascular diseases (CVD) have been linked to cognitive impairment and dementia. However, whether the association of CVD events and dementia differed by sex remains unclear.

Hypothesis:
We hypothesized that there might be a sex difference in the association between CVD events and dementia, and the effect of CVD on the risk of dementia might be greater in women than in men.

Methods:
We used cohort data from UK Biobank, a large population-based prospective cohort study that recruited 502 649 individuals ages 40- 69, between 2006 and 2010. Cox proportional hazards models were used to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between CVD (including coronary heart diseases (CHD), stroke and heart failure) and incident dementia (including all-cause dementia, Alzheimer's Disease (AD), vascular dementia and dementias in other diseases classified elsewhere).

Results:
Overall, 482 185 (54.6% women) people with no prevalent dementia were included. After 10 (median) years follow-up, 5330 participants (46.9% women) developed dementia. The crude incidence rates were 10.1 for women and 13.8 for men, per 10,000 person-years. The HRs (95%CI) between any CVD events, un-overlapped CHD, stroke, heart failure and all-cause dementia in women were higher than the estimates in men, with an RHR (95%CI) of 1.25 (1.17, 1.34), 1.37 (1.23, 1.51), 1.15 (1.00, 1.34) and 1.16 (1.03, 1.31) respectively. Also, the HRs for AD of CHD and heart failure in women were higher than the estimates in men, with an RHR (95%CI) of 1.73 (1.48, 2.02) and 1.40 (1.14, 1.72) respectively. Nevertheless, the HRs (95% CI) between stroke and vascular dementia was higher in men (5.35, 4.07-7.04) than that in women (3.24, 2.14-4.92) (Table 1).

Conclusions:
There was a sex difference in the association between CVD events and dementia. The risk of CHD and heart failure for dementia was greater in women than in men.
Abstract 11956: Wharton Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles Improves Cardiac Performance Following Myocardial Injury
Authors: Kanashiro-takeuchi Rosemeire M , Bellio Michael , Takeuchi Lauro , Kulandavelu Shathiyah , Lee Yee-Shuan , Balkan Wayne , Hare Joshua M , Khan Aisha
Published: April 2024

Introduction:
Mesenchymal Stem Cells (MSC)-derived extracellular vesicles (EVs) are being considered as a therapeutic option for treatment of myocardial infarction (MI). We hypothesize that systemic delivery of Wharton’s Jelly (WJ)-MSC-EVs following injury will improve cardiac function and reduce scar size.

Methods:
C57Bl/6J male mice were subjected to MI by permanent ligation of the left anterior coronary artery. One-week post-MI, mice were randomized into placebo (PL)- and EV-treated groups. WJ-MSC-EVs isolated from healthy full-term human umbilical cords were injected into the jugular vein once a week for 6 weeks beginning at week 1 post-MI (n=14/group). Cardiac function was assessed using echocardiography before and after treatment, cardiac performance was assessed using pressure-volume loops, and Masson’s trichrome staining was used to assess myocardial infarct size.

Results:
Echocardiographic evaluation showed an increase in ejection fraction (EF, 21.9 ± 2.3% vs. 11.8 ± 1.4%) and cardiac output (CO, 15.2 ± 1.2 μl/min vs. 8.70 ± 1.0 μl/min) in the EV treated group compared to PL (p<0.05). Similarly, hemodynamic performance was improved indicating cardiac benefits of EVs. As depicted in Fig 1A-F, EV group showed improvement by an increase in the stroke work (SW), CO, EF and ventricular arterial coupling (Ea/Ees), while end-diastolic pressure-volume relationship (EDPVR) was reduced (*p<0.05, ***p<0.0001). EV treatment significantly reduced scar size (Fig 1G).

Conclusions:
Systemic delivery of EVs improved cardiac performance and reduced scar size following establishment of MI. Accordingly, WJ-MSC-EVs represent a potential therapeutic approach to attenuate impairment of cardiac function and scar size.
Abstract 11966: Combined Shear Stress-Molecular Imaging for the Evaluation of Bioresorbable Scaffold: Effect of Strut Thickness on the Endothelial Microenvironment and Early Inflammatory Response
Authors: Kim Sunwon , Nam Hyeong Soo , Park Hyun-Sang , Song Joon Woo , Ahn Jae Won , Kim Yeon Hoon , Kim Hyun Jung , Yoo Hongki , Oh Wang-Yuhl , Park Kyeongsoon , Kim Jin Won
Published: April 2024

Introduction:
We evaluated local endothelial shear stress (ESS) distribution and arterial healing response of a thin-strut bioresorbable scaffold (BRS, 100μm) compared to 157μm-thickness ABSORB.

Hypothesis:
Thinner-strut design is known to promote stent healing, however, there has been a lack of
in vivo
imaging evidence on how strut thickness affect healing process.

Methods:
BRS and ABSORB were implanted in left anterior descending and circumflex arteries of pigs (n=7). Detailed scaffolded-artery 3D model was reconstructed based on OCT. Scaffold-related inflammation response was serially assessed by OCT-near-infrared fluorescence (OCT-NIRF) molecular imaging using macrophage-mannose receptor-Cy7 as NIRF emitter.

Results:
On ESS analysis, regions with athero-prone low ESS were significantly greater in ABSORB than in BRS. OCT-NIRF structural-molecular imaging clearly visualized active inflammation at peri-strut regions (Figure). Arterial inflammation, quantified as target-to-background ratio, was significantly lower in thin-strut BRS than ABSORB at 2 weeks (p<0.01). A statistically significant inverse correlation was found between logarithmic transformed ESS and NIRF activity (p<0.0001, Figure), demonstrating direct immune-modulating effect of ESS. Serial imaging showed that inflammation activity decreased more rapidly in thin-strut BRS compared to ABSORB. Ex vivo confocal fluorescence microscopy and immunohistochemical analysis well corroborated the findings in vivo.

Conclusions:
Thin-strut BRS with favorable ESS profile was associated with less inflammation and rapid resolution of inflammation, demonstrating that strut-related changes in endothelial microenvironment affect early healing by modulating arterial immune response. Our novel imaging strategy enabling comprehensive evaluation of complex biomechanical interaction between scaffold, ESS, and vasculature is expected to enhance understanding of BRS biology.
Abstract 11984: Impact of Underlying Pulmonary Hypertension on In-Hospital Outcomes Among Patients With Septic Shock
Authors: Vasudeva Rhythm , Vindhyal Mohinder , Pothuru Suveen Krishna , Shah Zubair , gupta Kamal
Published: April 2024

Background:
Pulmonary Hypertension (PHTN) patients typically have chronic multiple comorbidities and are more vulnerable to acute clinical conditions leading to decreased survival. The impact of pulmonary hypertension on outcomes in patients with septic shock remains unknown.

Methods:
Adult patients with a diagnosis of septic shock were identified in the National Readmissions Database (NRD) between the years 2016-2017. Propensity matched retrospective cross sectional clinical outcomes were compared between patients with and without non-cardiac PHTN using appropriate statistical methods after nearest matching on a 2:1 ratio for several demographic, social and clinical variables. Patients with cardiogenic shock, aortic and mitral valvular heart disease, underlying systolic and combined heart failure (HF), and PHTN due to left heart disease were excluded from the primary analysis. Appropriate ICD-10 codes were used.

Results:
A total of 13,676 patients diagnosed with non-cardiac PHTN and septic shock were identified with a mean age of 68 years and 58.6% identified as females. Patients with PHTN had higher comorbidities, including hypertension, chronic pulmonary disease, renal failure, diabetes, CAD, and obesity. After matching, patients with septic shock and non-cardiac PHTN were noted to have a higher mortality (33.2% vs 31.3%, p < 0.001), greater vasopressor use (7.9% vs 6.6%, p < 0.001), higher rates of acute heart failure (1.1% vs 0.6%, p < 0.001), longer hospital stay (14.0 days vs 12.7 days, p < 0.001), and higher hospital costs ($196,411 vs $171,537), when compared to patients with septic shock and without PHTN. Rates of AKI were noted to be lower in patients with PHTN. Amongst stroke outcomes, minimal differences in ischemic strokes were noted. There were no MI outcomes observed.

Discussion:
PHTN is associated with worse mortality, morbidity, and resource utilization outcomes in patients admitted with septic shock, except AKI. These findings should be interpreted carefully given the administrative nature of the database, and the population cohort restricted to readmissions.
Abstract 11990: Insulin-Like Growth Factor Binding Protein 2 is a Novel Marker of Early Smooth Muscle Cell Phenotype Modulation in Thoracic Aortic Aneurysm
Authors: Pedroza Albert J , Dalal Alex R , Shad Rohan , Cheng Paul , Yokoyama Nobu , Nakamura Ken , Hiesinger William , Quertermous Thomas , Fischbein Michael P
Published: April 2024

Introduction:
Single cell RNA sequencing (scRNAseq) enables high resolution analysis of vascular smooth muscle cell (SMC) phenotype modulation in thoracic aortic aneurysm. Insulin-like growth factor binding protein-2 (
Igfbp2
) expression by SMCs is activated early in a murine Marfan syndrome (MFS) aortic aneurysm model.
IGFBP2
modulates IGF1 bioavailability and interacts directly with SMCs via integrins. We hypothesize that
IGFBP2
is a marker of early SMC modulation in human aortopathy.

Methods:
Surgically resected aortic aneurysm tissue was collected from patients spanning the clinical spectrum of monogenic aortopathies (
ACTA2, FBN1, TGFBR1 (n=2), TGFB2, or SMAD3
variants). Tissues were digested and processed for scRNAseq. SMC clusters from all patients were jointly analyzed with pseudotemporal trajectory analysis to reconstruct the SMC phenotypic continuum. Primary MFS human (n=5) aortic root SMCs underwent
IGFBP2
silencing via siRNA followed by bulk RNAseq.

Results:
scRNAseq identified two main SMC clusters, comprising 39% of all cells in the dataset, including a quiescent contractile SMCs and a modulated, synthetic subset. Pseudotemporal ordering generated a continuous ‘pseudotime’ scale inversely correlated with contractile gene (e.g.,
CNN1,
MYH11) expression, modeling gradual de-differentiation
in vivo
. We identified similar markers of late SMC modulation (e.g.,
TNFRSF11B
,
MMP2, CYTL1, COL1A1
) in patients of all genotypes.
IGFBP2
expression showed comparatively earlier activation and peak with reduced expression late in pseudotime. Silencing
IGFBP2
in human MFS SMCs
in vitro
significantly depressed contractile gene expression.

Conclusions:
SMC modulation occurs in consistent pattern across hereditary aortopathy subtypes.
IGFBP2
activation occurs early in this trajectory, marking cells in phenotypic transition.
IGFBP2
may promote contractile phenotype maintenance, presenting a novel pathway for potential therapies.
Abstract 11991: Effects of Clozapine at Different Doses on Blood Pressure and Renal Sodium Transporters in Mice
Authors: Ren Zhiyun , Wang Weiwan , Zhang Chenyang , Ye Min , Wang Xiaoyan
Published: April 2024

Introduction:
one of major side effects of clozapine (common antipsychotic drug) is hypertension. Kidney regulates blood pressure by initiating and responding to renin-angiotensin-aldosterone system (RAAS) physiologically and pathophysiologically;the pathogenesis of hypertension is linked to, generally, the increases in the protein expressions and functions of renal sodium transport proteins along the nephron with or without RAAS activation.

Methods:
we examined the blood pressures (BP) and protein expressions of major sodium transport proteins profiled along the renal tubules in the C57Bl6/J male mice (9 weeks old, n=4-5/group) treated with clozapine at three doses of 5,10 and 20 mg/ kg for 1 week via intraperitoneal injection.

Result:
blood pressures (tail-cuff, BP98A, softron, Japan) were higher in clozapine at 20mg/kg/day than vehicle (SBP: 130±1.64 vs 109±1.39, DBP: 87 ±4.12 vs 69±2.10 mmHg, n=5/group) and not altered at 5 & 10 mg/kg/day. BW was similar between groups. There were no differences in serum/urine creatinine and electrolytes except for a slight increase in serum sodium at dose of 20 mg/kg (152.8±0.71 vs 150.6±0.40, mmol/L).The renal protein expressions of NaPi2 (western blotting, 199±26 , % of vehicle), NKCC2(184±20), NCC(213±14), and ENaC-α(217±47)were higher at 20 mg/kg than vehicle. No increases were found in protein expressions of NHE3, αNKA, ENaC-β and ENaC-γ. The expressions of renin, AT1R and ACE at 20mg/kg were similar between groups while ACE2 was decreased (42±10). Renal protein expression of NKCC2 was increased in 5mg/kg (360±80, % of vehicle) and 10mg/kg (247±50) groups; NCC was increased at 5 mg/kg (175±9); α NKA was increased in 5mg/kg (216±5) and 10mg/kg (163±2) groups. Additional mice were treated with clozapine at 20mg/kg/day via osmotic mini-pump for 1 week (mini-pump) or administrated by intraperitoneal injection for 2 weeks (2wks). Increases of renal NKCC2 (mini-pump:180±21, 2wks:153±18) and NCC (mini-pump:171±22, 2 wks:160±23) were also found in those models.

Conclusions:
increases of renal sodium transport proteins, mainly NCC and NKCC2, contribute to the dose-related increase of BP in mice treated with clozapine and may play an important role in the pathogenesis of theclozapine-induced hypertension.
Abstract 12333: Intravenous Sotalol for Adenosine Refractory Supraventricular Tachycardia
Authors: Valdes Santiago O , Howard Taylor , Pham Tam D , Rochelson Ellis , Lam Wilson W , Miyake Christina , Kim Jeffrey
Published: April 2024

Introduction:
For re-entrant supraventricular tachycardia (SVT) that is refractory to adenosine, options of intravenous (IV) anti-arrhythmics for acute conversion are limited. IV sotalol has become more readily available, but experience in children with adenosine refractory SVT is limited.

Hypothesis:
IV sotalol is safe and effective for acute termination of adenosine refractory re-entrant SVT.

Methods:
A retrospective study of all pediatric patients receiving IV sotalol for SVT from 2016-2021, that had previously failed to convert with adenosine administration was performed. SVT consisting of orthodromic reciprocating tachycardia were included, all other supraventricular arrhythmias were excluded. Patient demographics, presence of congenital heart disease (CHD), arrhythmia type, efficacy of IV sotalol use and adverse effects were evaluated. For patients that failed to convert after the administration of adenosine a 1 mg/kg IV bolus of sotalol was given over 1 hour. Complete efficacy was defined as SVT terminating with IV sotalol bolus, partial efficacy was defined as adenosine converting SVT during or after the sotalol bolus, when adenosine had previously failed to convert SVT.

Results:
A total of 20 separate SVT events were treated with IV sotalol in 19 patients (53% male). Wolff-Parkinson-White syndrome was present in 5/19 patients (26%), and 9/19 patients (47%) had associated CHD. Patients had a median age of 0.24 yrs (IQR 0.03-6.86 yrs), median weight 4.30 kg (IQR 3.61 - 25.55 kg). Ventricular function prior to IV sotalol use was mildly or moderately depressed in 5/19 (26%) patients. Of the 20 events 5 (25%) were during the acute post-operative period. A single IV sotalol bolus was effective in converting adenosine refractory SVT in 19/20 (95%) events, with 16/20 (80%) having complete efficacy and 3/20 (15%) with partial efficacy. Median time to conversion was 0.5 hours (IQR 0.3-0.98 hours). No patient experienced an adverse effect during IV sotalol bolus.

Conclusions:
IV sotalol is a safe and effective antiarrhythmic option for acute conversion of adenosine refractory SVT.
Abstract 12338: Promotion of Arteriolar Differentiation of Vascular Endothelial Cells by PKD-1/CD36 Signaling-Mediated Chromatin Remodeling
Authors: Gutierrez-Garcia Ana K , Spangler Emily , Beck Adam , Ren Bin
Published: April 2024

Vessel narrowing and occlusions reduce blood supply to end tissues, leading to myocardial infarction in the heart or tissue loss in the peripheral vasculature. Effective approaches are needed to establish de novo arteriogenesis to treat these conditions. An essential first step is to understand mechanisms of arteriolar differentiation, in which transcriptional reprogramming of vascular endothelial cells (ECs) may be critical. Our previous studies indicate that protein kinase D (PKD-1) is required for arterial differentiation and plays an essential role in proarteriogenic reprogramming via transcriptional inhibition of antiangiogenic receptor CD36 via histone deacetylase HDAC7. We hypothesize that PKD-1/CD36 signaling initiates an epigenetic reprogramming of ECs for arteriolar differentiation via chromatin remodeling. To test this hypothesis, we isolated primary heart and lung ECs from wild-type control, EC-specific cd36 KO or pkd-1 KO mice. Total RNA was extracted for expression of arteriogenic genes by RT-qPCR. The proteins were collected for Western blotting and ChIP assays. Our results showed that when CD36 was downregulated in primary ECs from hearts and lungs, the expression levels of PKD-1 and arteriogenic genes EphB2 and DLL4 were significantly elevated compared to controls (p < 0.05). Intriguingly, we observed a significant increase in protein expression of neuropilin1. In contrast, in heart ECs from the EC-specific pkd-1 KO mice, arteriogenic gene expressions were downregulated whereas CD36 expression was significantly upregulated. Using the ChIP assay, we measured the interactions between H3K9 on the CD36, DLL4, or EphB2 promoters using ECs from EC-specific cd36 and pkd-1 KO mice. In conclusion, our results indicate that an epigenetic reprogramming regulates arteriolar differentiation at a transcriptional level by chromatin remodeling. PKD-1 signaling may dictate CD36 transcriptional levels, thereby reprogramming ECs for arteriolar differentiation by inducing an arteriogenic gene signature, which may contribute to de novo arteriogenesis under ischemic conditions.