bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15090: At-Risk Financial Status is Associated With Less Favorable Outcomes in Patients With Left Ventricular Assist Devices
Authors: Honan Kevin A , Bhardwaj Anju , Erdhem Saliha , Kumar Sachin , Kwak Min Ji , Mosele Elizabeth , Nascimbene Angelo , Patel Manish K , Salas De Armas Ismael , Nathan Sriram , Akkanti Bindu , Gregoric Igor D , Kar Biswajit
Published: June 2023

Background:
Few studies have investigated the impact of psychosocial determinants in patients with left ventricular assist devices (LVADs).

Methods:
We conducted a single-institution, retrospective review of patients hospitalized for index LVAD implant (January 2013 to July 2019). Patients underwent a comprehensive psychosocial evaluation conducted by certified clinical transplant social workers. Each evaluation included psychosocial determinants of health:
Psychiatric illness, Compliance, Substance abuse, Family support, Level of understanding, Adequate housing/transportation, and financial status
. Factors such as financial status carried their separate scoring grade (0-4 scale); patients scoring 0 were counted as ‘high-risk,’ while those scoring >3 (adequate income) were low-risk (Table 1).

Results:
Of 330 patients, 211 had comprehensive psychosocial risk assessment, while the others had abbreviated assessments due to acuity. A total of 93 patients had eventual death after device implantation. Maximum follow-up was 3280 days. Financial status showed significant association with survival on univariate Cox-regression analysis. Those with inadequate finances had lower survival (P = .014; Figure 1). On multivariate Cox-regression analysis, the impact of financial status on survival decreased.

Conclusions:
Socioeconomic assessments of patients eligible for LVADs are important, and further analysis is needed to identify relationships between psychosocial determinants and outcomes. Identification of specific causal relationships that predict worse outcomes in this patient population will benefit the field.
Abstract 15102: Short- versus Long-Term Recurrence of Ventricular Tachycardia in Non-Ischemic Cardiomyopathy: Is It Due to Incomplete Ablation During the Index Procedure or Progression of the Disease? Results From a Single-Center Study
Authors: Mohanty Sanghamitra , Shetty Sai Shishir , Baho Karim , Della Rocca Domenico G , QUINTERO MAYEDO ANGEL , MacDonald Bryan , gianni carola , Morris Trevor , Asfour Issa , Kessler Danielle , Bassiouny Mohamed , Gallinghouse G , Burkhardt John , Horton Rodney , Al-Ahmad Amin , Di Biase Luigi , Natale Andrea
Published: June 2023

Background:
Non-ischemic cardiomyopathies (NICM) occur in the absence of contributory coronary artery disease or significant valvular heart disease. This study examined if VT recurrence post-scar-homogenization in NICM patients was due to progression of the disease after successful ablation or incomplete ablation during the index procedure.

Methods:
Consecutive NICM patients receiving redo procedure after their 1st VT ablation were included. All patients underwent bipolar substrate mapping with standard scar settings of normal tissue >1.5 mV and severe scar <0.5 mV. Endocardial scar homogenization was followed by heparin reversal with protamine and subsequent epicardial ablation.

Disease progression

was defined as extension of index scar area or appearance of new scar and decline in the baseline left ventricular ejection fraction (LVEF).

Incomplete ablation

was described as ablation within the index scar area that was ablated in the earlier procedure. Recurrence within 12 months was considered as
early recurrence
.

Results:
A total of 310 NICM patients (age: 60±13.5 years; male: 231 (74%); LVEF: 37±11%) undergoing their first VT ablation procedure were followed up for 7 years, of which 38 (12.2%) experienced recurrence and underwent re-ablation. Of the 38, 13 received repeat ablation at 5.07±2.56 months (
early recurrence
) and the remaining 25 patients had the redo at 40±21.78 months (
late recurrence
). In these 38 patients, mean LVEF was significantly lower at redo (pre-index: 35.3±10.6; pre-redo: 30.2± 7.07%, p=0.015).
In the early-recurrence group
, 10 (77%) had ablation sites located within the index scar (incomplete ablation) and 3 (33%) had extension of the index scar area (disease progression) detected. Index scars were
mostly mid-myocardial
(11, 84.6%).
In the late-recurrence cohort
, extension of the index scar area was detected in 12 (48%) and new scar were mapped in 19 (76%); none of these patients had incomplete ablation noted.

Conclusion:
In NICM patients, VT recurrence within 1-year of index procedure was mostly associated with incomplete ablation of mid-myocardial scars, whereas disease progression evidenced by detection of new scar, extension of preexisting scar and decline in LVEF was prevalent in patients with very late recurrence.
Abstract 15113: C-cbl E3 Ubiquitin Ligase Regulates Cardiomyocyte Proliferation and Cardiac Regeneration
Authors: Le Qui A , Guo Xinji , Kolpakov Mikhail A , Turner Mallory , Bkhache Meriem , Rafiq Khadija , Du Binbin , Addya Sankar , Wang Tao , Sabri Abdelkarim
Published: June 2023

Background:
Neonatal mammalian hearts display considerable regenerative capacity following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by post-natal day 7. Previous studies have shown the role of receptor tyrosine kinases (RTKs) on cardiomyocyte proliferation and cardiac regeneration. However, the mechanisms that control RTK turnover and signaling during and beyond the regenerative window of the heart remain largely unknown.

Hypothesis:
This study investigates the role of the proto-oncogene Casitas b-lineage lymphoma (c-Cbl), an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets RTKs, on cardiomyocyte proliferation and cardiac regeneration following myocardial infarction (MI).

Methods and Results:
c-Cbl expression was downregulated during post-natal development and re-expressed in the adult heart following MI. RNA-sequencing studies reveal a distinct transcriptional profile in c-Cbl-deficient mouse hearts, of which c-Cbl deletion substantially delayed cardiomyocyte maturation and enhanced cardiomyocyte proliferation. c-Cbl deletion also extended the regenerative window for post-natal mouse hearts following MI and enhanced the ability to recover following MI with improved myocardial function, reduced scar formation, and increased cardiomyocyte cell-cycle activity. Mechanistically, c-Cbl E3 ubiquitin ligase activity was markedly enhanced in the adult than neonatal heart following MI, along with increased ubiquitination and downregulation of key RTKs involved in cardiomyocyte proliferation. Intriguingly, adenoviral expression of a c-Cbl mutant deficient in E3 ligase enhanced RTK signaling and promoted cardiomyocyte proliferation in vitro.

Conclusions:
These results reveal c-Cbl as a critical regulator of cardiomyocyte proliferation and a potential therapeutic target for the maintenance of cardiac regeneration and function following MI.
Abstract 15121: Specialty Care Visits and Likelihood of Mortality for Children With Congenital Heart Disease
Authors: Parker Devin , Stabler Meagan , Mackenzie Todd , Zimmerman Meghan , Shi Xun , Brown Jeremiah R
Published: June 2023

Introduction:
Congenital heart disease (CHD) is the most common birth defect and is estimated to affect nearly 37,500 infants born each year in the United States. Children with CHD have complex, nuanced, healthcare needs and frequently require multi-specialty care. The relationship between specialty care utilization and survival for children with CHD is not well known.

Methods:
We analyzed all payer claims data (APCD) from Colorado from 2012-2019. Children with CHD were identified by applying harmonized ICD-9-CM and ICD-10-CM diagnoses codes. We included children with CHD < 18 years of age who resided in Colorado, had a documented zip code, and had at least one healthcare claim. Specialty care providers were uniquely identified by their National Provider ID. Mortality was defined by discharge status. We evaluated the relationship between specialty care provider visits and mortality using logistic multivariable modeling.

Results:
There were 24,784 children diagnosed with CHD in Colorado from 2012 - 2019. Of those, 22,413 (90.4%) children had at least one specialty care visit and 465 (2.1%) died during the study period. Children that died had an average of 60 visits per year, while children that survived had an average of 29 visits (p=<0.001). Children primarily commercially insured by are 25% less likely to experience death (OR: 0.75, 95% CI (0.58 - 0.97), p value: <0.001). Children with greater CHD disease severity or presence of a genetic disorder are nearly 2 times more likely to die, and children in the highest community level quartile are less likely to die.

Conclusions:
In our cohort of children diagnosed with CHD from 2012 - 2019, there was a significant association with the frequency of specialty care visits and likelihood of death. We found that the primary insurer, level of disease severity, presence of any genetic disorder and community level household income were significantly associated with higher likelihood of death.
Abstract 15122: Escalation Strategies, Management, and Outcomes of Acute Myocardial Infarction-Cardiogenic Shock Patients Receiving Percutaneous Left Ventricular Support
Authors: Patlolla Sri H , Vallabhajosyula Saraschandra
Published: June 2023

Introduction:
Despite well-established device selection algorithms, there remain wide variations in mechanical circulatory support (MCS) device utilization in patients with cardiogenic shock complicating acute myocardial infarction (AMI-CS). Further, there are limited national-level data on the contemporary practices of MCS device use.

Methods:
To evaluate national utilization patterns of MCS devices, we identified adult admissions (>18 years) with AMI-CS from the HCUP-NIS data (2005-2017). Use of MCS devices including intraaortic balloon pump (IABP), percutaneous left ventricular assist devices (pLVAD) (Impella/Tandem Heart), and extracorporeal membrane oxygenation (ECMO) during hospitalization was identified. We evaluated trends in the initial MCS device used (IABP alone, pLVAD alone, or ≥2 MCS devices), device escalation, bridging to durable LVAD/heart transplantation, and predictors of in-hospital mortality and device escalation.

Results:
Among a total of 327,283 AMI-CS admissions in this 13-year period, 132,146 (40.2%) had an MCS device with information on timing of placement. IABP, pLVAD, ≥2 MCS, and ECMO devices were used as initial device in 120,928 (92.0%), 8,202 (6.2%), 2,305 (1.7%), and 711 (0.1%) admissions, respectively. Most admissions were maintained on initiated MCS device with 1-1.5% being escalated (IABP to pLVAD/ECMO, pLVAD to ECMO). The median time to escalation across all devices categories was 2 (IQR 1-4) days. Urban, medium, and large-sized hospitals, and acute multiorgan failure were significant independent predictors of MCS escalation. In admissions receiving MCS, escalation of MCS device was associated with higher in-hospital mortality (adjusted OR 1.56, 95% CI 1.38-1.75;
p
<0.001). Admissions receiving durable LVAD/heart transplantation increased over time in those initiated on pLVAD and ≥2 MCS devices resulting in lower in-hospital mortality.

Conclusions:
In this 13-year study, escalation from initial MCS device was associated with higher in-hospital mortality suggestive of higher acuity of illness. However, the observed increase in number of durable LVADs or heart transplantations may be an indication of the utility of these MCS devices as successful bridge therapies.
Abstract 15128: Are We Underestimating the Incidence of Significant Ventricular Ectopy in Pediatric Patients With Post-Covid Vaccine Myocarditis?
Authors: Del Grippo Erica L , Connolly Sean , Geary Elaine , Temple Joel , Thacker Deepika
Published: June 2023

Background:
The development of mRNA vaccines was essential in combatting the COVID-19 pandemic. Emergency use authorization for COVID-19 vaccine was granted to adolescents aged 12 and older in May 2021. Subsequently, an increase in myocarditis was observed related to the mRNA vaccine. Previous reports estimate a 5% incidence of ventricular arrhythmias in patients with vaccine-associated myocarditis.

Hypothesis:
The incidence of ventricular ectopy in patients with post-COVID vaccine myocarditis is higher than previously described.

Methods:
We analyzed data retrospectively for patients admitted to our cardiac center with clinically suspected myocarditis who received COVID-19 vaccine within 30-days prior to onset of symptoms and had no other clinical cause for myocarditis. We separated this cohort into 3 groups based on the presence of rhythm monitoring post discharge: normal monitor post discharge (Lown grade 0 or 1), abnormal monitor post discharge (Lown grade ≥ 2), and no monitor post discharge. Data are shown as mean ± standard deviation.

Results:
We included 16 patients with a mean age of 14.9 ± 3.1 years. 12 patients were discharged with ambulatory monitoring and 3 were categorized as abnormal (25%). Abnormal findings included non-sustained ventricular tachycardia, ventricular ectopy with bigeminy and trigeminy patterns, and sustained monomorphic ventricular tachycardia. 1 patient was readmitted for sustained ventricular tachycardia. Mean troponin levels were higher in the arrhythmia group (17.3 ±4) compared to the non-arrhythmia group (4.3 ±4.3). 2 of the 3 patients in the arrhythmia group had myocardial edema on cMRI. Only one patient had LGE.

Conclusion:
At our center, 25% of patients with post-COVID vaccine myocarditis experienced ventricular arrhythmias, and these patients had higher troponin levels during acute illness. Awareness of this increased rate of arrhythmia is necessary to safely monitor patients with post-COVID vaccine myocarditis.
Abstract 15148: Contemporary Trends of Antibacterial Envelope Use to Prevent Cardiac Implantable Device Infection: Insights From the National Readmission Database
Authors: Shatla Islam , Mujer Mark , Baker Preston , Kashlan Besher , Pieters Zachary , Elkaryoni Ahmed , Wimmer Alan P
Published: June 2023

Introduction:
Local antibiotic delivery using an antibacterial envelope (AE) was shown to reduce major cardiac implantable electronic devices (CIEDs) infections in a controlled trial. We sought to assess the effect of AE use on CIED infection rates in subsequent clinical practice in the U.S.

Methods:
Using the Nationwide Readmissions Database and ICD 9/10-PCS codes, we identified patients who had a CIED implanted between 2010 and 2018. Patients were stratified according to the use of an AE. Outcomes were CIED infection rates as well as trends and predictors of AE use.

Results:
A total of 866,245 patients underwent CIED implantation between 2010 and 2018, with 8489 (1.0%) having an AE implanted during the same index admission. AE use showed an increasing pattern from 0.2% in 2012 up to 3.3% in 2018, p<0.001. After excluding the last 6 months of each calendar year to allow for 6 months of follow-up data, a total 438,299 patients had a CIED implanted with 3938 (0.9%) receiving an AE. The rate of CIED related infection during 6-months post-implantation was lower among patients who had an AE (1.2% vs. 2.2, P<0.001), and this difference persisted after adjustment using a multivariable regression model (OR, 0.53; 95% CI: 0.39-0.71, P<0.001). Some patient factors (hypertension, heart failure, chronic kidney disease, atrial fibrillation and obesity), and hospital characteristics were independent predictors of increased likelihood of AE use during CIED placement (Table 1).

Conclusions:
There is an up-trending pattern of AE use during CIED implantation. The use of these envelopes is associated with a lower risk of CIED related infection.
Abstract 15153: Inhibition of the Tumor Suppressor Wwox Expression Alters Mitochondrial Dynamics in PASMC
Authors: Gomes Marta T , Polidoro Rafael , Bai Yang , Machado Roberto F
Published: June 2023

Introduction:
Pulmonary arterial hypertension (PAH) contributes to the morbidity and mortality of several patients with different pulmonary and cardiac diseases. Among other factors, the pathogenesis of PAH involves exaggerated pulmonary artery smoot muscle cell (PASMC) hyperproliferation, resistance to apoptosis and energy metabolism shift associated with alterations in mitochondrial metabolism and dynamics. The WW domain-containing oxidoreductase gene (
WWOX
) is a tumor suppressor gene that has the ability to interact with a large number of proteins, exerting its activity through a wide variety of molecular actions in specific cells. WWOX loss affects cell proliferation, motility, and deregulates expression of genes involved in cell cycle regulation, metabolism, and DNA damage in a variety of cancers. Considering that a similar phenotype is observed in cancer cells and PAH, we sought to investigate whether the loss of WWOX in PASMC is associated abnormalities of mitochondrial metabolism and dynamics in PAH.

Methods and Results:
In PASMC, inhibition of WWOX expression by short-interfering RNA (siRNA) decreased oxygen consumption by 30% when compared with siRNA control. Dysregulation of mitochondrial bioenergetics in WWOX-silenced PASMC was attributed to modulation of the oxidative state of mitochondrial electron transport chain proteins, showing that succinate dehydrogenase (SDH)(complex II) expression decreased by 15% in relation to siRNA control. JC-1 and mitotraker red CMXROS staining demonstrated that WWOX- silenced PASMC had hyperpolarized and fragmented mitochondria that generated more reactive oxygen species than the control. Changes in mitochondrial dynamics were detected with increased phosphorylation levels of the fission protein, dynamin-related protein 1 (DRP-1) and, decreased Mitofusin 2 and 1 protein levels, positive regulators of mitochondrial fusion.

Conclusion:
Loss of WWOX expression causes changes in PASMC mitochondrial metabolism and dynamics stimulating these cells to use different resources as a way to reprogram their metabolism and ensure their survival. These alterations may contribute, for example, to the stimulation of vascular remodeling, which consequently promote the pathogenesis of PAH.
Abstract 15164: Refractory Shock Following Ingestion of Gamma Hydroxy Butyrate Laced With Xylazine
Authors: Hasnie Ammar , Schormann Sebastian , Daley Lauren V , Minish Jordan , Lahaye Reed , Krick Stefanie
Published: June 2023

Case:
A 35 year old male with a complex psychiatric history including previous suicide attempts was brought to the emergency department after being found on a sidewalk with bradycardia and bradypnea by emergency medical services (EMS). He responded to naloxone administered by EMS and admitted to using heroin, gamma hydroxyl butyrate (GHB), and rohypnyol prior to becoming unconscious. On arrival, his vitals showed a sinus heart rate at 60, decreased respiratory rate with normal oxygenation, hypotension with systolic blood pressures in the 50’s, and hypothermia with a temperature of 95 degrees Fahrenheit. On physical exam his heart rate and rhythm were regular, lungs were clear to auscultation, he had pinpoint pupils, and was perfusing his extremities well with normal capillary refill without diaphoresis. A bedside echocardiogram showed normal left ventricular ejection fraction without signs of cardiogenic shock. He was subsequently started on two pressors but continued to clinically worsen requiring overmaxed doses of five pressors including Angiotensin II. He continued to clinically decline with worsening renal failure requiring CRRT therapy and remains ventilator dependent.

Discussion:
This patient was admitted to the intensive care unit for profound vasoplegic shock. The etiology of his shock was due to a veterinary drug called xylazine. Xylazine is a horse tranquilizer which is commonly laced in drugs of abuse including GHB. It’s an alpha 2 agonist which causes decreased sympathetic outflow and decreased norepinephrine release leading to a clinical presentation including profound hypotension, bradycardia, CNS depression, and miosis. While it can mimic opioid toxicity patients tend to have preserved respiratory status and transiently respond to painful stimulation. Patients who don’t concomitantly use opioids, do not typically respond to naloxone. It is critical to consider this in the differential in patients with an opioid toxidrome who don’t respond to naloxone. The treatment for xylazine overdose is supportive care of their hemodynamics. The half-life of the drug is around 48 hours but can persist for several days. While xylazine overdose generally carries a good prognosis, it can still lead to devastating consequences.
Abstract 15175: Differentiation Between Intramural Hematoma and Thrombosed False Lumen in Aortic Dissection Using Latest Spectral Computed Tomography With Dual-Layer Detector
Authors: Funabashi Nobusada , Misumi Kazuo
Published: June 2023

Introduction:
Differentiating intramural hematoma (IH) from a thrombosed false lumen (FL) in aortic dissection (AD) is difficult by CT since both are regarded as AD without a tear. IH may be caused by vasa vasorum rupture, and therefore differentiation should be by histology. Spectral CT with a dual layer detector can generate CT images at any keV after ordinary acquisition using virtual monoenergetic settings (VMS).

Hypothesis:
Using spectral CT (range 40-200 keV), and a spectral distribution of CT values for aortic true lumen (TL) and FL, we can differentiate IH from thrombosed FL in AD in early and late-phase enhanced CT values.

Methods:
We performed enhanced 128-slice spectral CT 7500 (Philips) scans with a dual-layer detector in 8 patients (5 males, 71±14 years), with suspected IH or thrombosed FL in AD in the ascending aorta (Group 1), and 6 patients (4 males, 67±12 years) with thrombosed FL in AD in the descending aorta (Group 2). VMS images at various keV values were created from spectral-based images. We measured TL, FL or IH lumens in axial images at each keV in early and late phases using contrast.

Results:
On spectral profile analysis, in Group 1, lower keV values were associated with almost no and slightly increased mean CT values for FL or IH, in early and late phases using contrast. In Group 2, lower keV values were associated with slightly and moderately increased mean CT values for FL, in early and late phases using contrast. The degree of increments in CT values in lower keV images in late phase with contrast was significantly smaller for FL or IH in ascending aortas (n=8) than for FL in descending aortas (n=6) (P<0.05).

Conclusions:
On CT, TL, FL, and IH lumens, in early and late phases using contrast are unique. IH may be caused by vasa vasorum rupture and thrombosed FL in AD spreading contrast in late phase. This may cause a difference in the degree of increments in CT values in lower keV images in late phase using contrast for FL or IH in the ascending aorta and for FL in the descending aorta.
Abstract 15180: Cerebral Blood Flow Measured by Mri is a Key Translational Hallmark of Brain Injury in Experimental Models of Hypertension-Induced Cognitive Impairment
Authors: Carnevale Lorenzo , Carnevale Raimondo , Perrotta Marialuisa , Mastroiacovo Francesco , Carnevale Daniela , Lembo Giuseppe
Published: June 2023

While several works pointed out the epidemiological associations between hypertension and dementia, the underlying mechanisms are still relatively unknown. In this work we focused on the application of translational tools like MRI to investigate the brain injury induced by hypertension and characterized by cognitive impairment and neuroinflammation. Cerebral hypertension was induced in mice by transverse aortic constriction (TAC) or sham procedure, as previously demonstrated by our group. We characterized cerebral blood flow (CBF) by 7T MRI, measuring the cerebral tissue blood prefusion. Morris Water Maze (MWM) was used to evaluate cognitive function in hypertensive and normotensive mice. Cortical microvasculature was analyzed in histological brain sections. A group of mice was treated with an antibody neutralizing IFNy, a key proinflammatory cytokine induced by hypertension. TAC mice showed a marked cerebral hypoperfusion, with CBF reduction in cortex (Sham: 96.58 vs TAC: 74.25 mL/100g/min p=0.024) and hypothalamus (Sham: 140 vs TAC: 121.4 mL/100g/min p=0.027). Tissue analysis revealed a reduction in capillary density defined as portion of field of view (FOV) occupied by capillaries (Sham: 11.3% vs TAC: 7.7%, p=0.004) and loss of their integrity in the cortex of hypertensive mice, defined as pericyte coverage percentage in the FOV (Sham: 79% vs TAC: 36%, p=0.01). Finally, the impairment in cognitive function measured by the MWM correlated with the CBF measures (r
2
:0.407, p=0.01). In the end, we subjected TAC mice to anti-IFNy treatment and analyzed the effects on brain vasculature assessed in vivo by MRI and ex vivo by histology. We observed that, while leaving unchanged the hemodynamic challenge on the brain, the treatment induced a global rescue in CBF (TAC: 99.85 vs TAC anti-IFNy: 116 mL/100g/min p=0. 008) and a strong correlation between MRI-measured CBF and microvascular density (r
2
:0.471, p=0.002). In conclusion, CBF evaluated by MRI is a key translational hallmark of hypertensive brain injury, and its evaluation in the clinical setting can provide insights on cerebral microvasculature health.
Abstract 15215: Autophagy Inhibition Attenuate the Development and Progression of Pulmonary Hypertension
Authors: Tang Haiyang , Bao Changlei , Wang Jian , Carew Jennifer S. , Yuan Jason
Published: June 2023

Introduction:
Autophagy plays an important role in the pathogenesis of pulmonary hypertension. However, the potential therapeutic benefit of autophagy inhibition remains undetermined.

Hypothesis:
ROC-325 was developed as a novel small molecule lysosomal autophagy inhibitor that has demonstrated significantly more potent anticancer activity than the antimalarial drug hydroxychloroquine (HCQ).

Methods:
Rats with monocrotaline-induced PH (MCT-PH) and hypoxia/Sugen-induced severe PH were treated with ROC-325 and the related effects on echocardiography, hemodynamics, right ventricle hypertrophy, and pulmonary vascular remodeling were assessed. Pulmonary arterial pressure (PAP) and isometric tension were measured in isolated perfused/ventilated mouse lungs and rat PA rings. The in vitro effects on ROC-325 on autophagy, proliferation, viability, apoptosis and endothelial nitric oxide (NO) synthase (eNOS)-NO signaling were tested in human and rat pulmonary artery smooth muscle cells (PASMCs) as well as human pulmonary artery endothelial cells (PAECs) and rat pulmonary microvascular endothelial cells (PMVECs).

Results and Conclusions:
The therapeutic benefits of a novel lysosomal autophagy inhibitor, ROC-325, in experimental pulmonary hypertension (PH) models. Specifically, ROC-325 treatment prevents the development of monocrotaline (MCT)-induced PH, right ventricular dysfunction, and pulmonary vascular remodeling, and reverses the progression of established MCT-PH. Meanwhile, ROC-325 treatment attenuates high K
+
or alveolar hypoxia-induced pulmonary vasoconstriction. Mechanistically, in PASMC and PAEC, ROC-325 inhibits autophagic pathways, reduces hypoxia induced-hypoxia inducible factor (HIF) accumulation and blocks endothelial nitric oxide (NO) synthase (eNOS)-NO signaling activation. These studies illustrate the discovery of ROC-325 as a novel promising agent for PH therapy.
Abstract 15218: Hereditary Transthyretin Cardiac Amyloidosis in a Patient at High Risk for Plasma Cell Dyscrasias: A Complex Diagnostic Work-Up
Authors: Calhoun Avery E , Azobou Tonleu Franck , Brown Matthew T , Ogunniyi Modele O
Published: June 2023

Background:
Cardiac amyloidosis (CA) is most commonly caused by the infiltration of misfolded amyloid transthyretin (ATTR) or light chain (AL) molecules in the myocardium. The workup for CA requires serum assessment to exclude the rapidly progressive AL subtype before imaging to assess the more common and indolent ATTR form. The diagnostic algorithm has the potential to become complex as in this case about a woman with Sjogren’s syndrome which predisposes to plasma cell dyscrasias.

Case:
A 68-year-old female with congenital long QT syndrome requiring implantable cardioverter-defibrillator (ICD), bilateral carpal tunnel, and recent diagnosis of Sjogren’s syndrome was found to have new systolic heart failure during workup for interstitial lung disease. Labs revealed pancytopenia, abnormal kappa/lambda ratio (2.25), and polyclonal gammopathy on immunofixation. Echocardiogram showed moderately reduced systolic function with an ejection fraction of 35-40% and moderate concentric left ventricular hypertrophy.

Decision-making:
Cardiology obtained cardiac magnetic resonance imaging (CMR) that returned indeterminate due to ICD artifact. Hematology performed a bone marrow biopsy that was negative for plasma cell dyscrasia, though stained positive for amyloid on congo red with mass spectrometry revealing the valine 142 isoleucine (Val142Ile) amino acid substitution consistent with hereditary ATTR-CA. To definitively assess for endomyocardial ATTR involvement the patient was sent for cardiac scintigraphy using 99mTc-labeled pyrophosphate which returned negative with a cardiac to contralateral lung uptake ratio of 1.001 and visual grade of 0. With suspicion still high, an endomyocardial biopsy was pursued and stained positive for congo red with mass spectrometry confirming hereditary Val142Ile ATTR-CA, allowing for tafamidis initiation.

Conclusion:
We present a complex diagnostic case of ATTR amyloid in a patient who is at high risk for plasma cell dyscrasias with an abnormal kappa/lambda ratio, non-diagnostic CMR, and negative nuclear scan. Despite significant advances in imaging techniques allowing for less invasive diagnostics, this case highlights the role of endomyocardial biopsy in complicated cases.
Abstract 15223: Insights Into Myocardial Programming in SARS-CoV-2 Infection Using Spatial Transcriptomics
Authors: Gastanadui Maria Gabriela , Margaroli Camilla , Benson Paul , Song Chunyan , Viera Liliana , Xing Dongqi , Wells James , Patel Rakesh , Gaggar Amit , Payne Gregory A
Published: June 2023

Introduction:
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is linked to thrombotic and cardiovascular events. Endothelial cell infection was initially proposed to initiate vascular events; however, this has sparked growing controversy. Significance of myocardial infection also remains unclear.

Hypothesis:
Our objective was to examine coronary endothelial and myocardial programming in patients with severe COVID-19 with digital spatial transcriptomics.

Methods:
Autopsy-derived cardiac tissue from control (n = 4) and COVID-19 (n = 8) patients underwent spatial transcriptomic profiling to assess differential expression patterns in myocardial and coronary vascular tissue. Our approach enabled transcriptional profiling
in situ
with preserved anatomy and unaltered local SARS-CoV-2 expression. In so doing, we examined paracrine effect of SARS-CoV-2 infection in cardiac tissue.

Results:
We observed heterogeneous myocardial infection that tended to colocalize with CD31 positive cells within coronary capillaries. Despite these differences, COVID-19 patients displayed a uniform and unique myocardial transcriptional profile independent of local burden. Segmentation of tissues directly infected with SARS-CoV-2 showed unique, pro-inflammatory expression profiles including upregulated mediators of viral antigen presentation and immune regulation. Infected cell types appeared to primarily be capillary endothelial cells as differentially expressed genes included endothelial cell markers (Figure 1). However, there was limited differential expression within the endothelium of larger coronary vessels.

Conclusions:
Our results highlight altered myocardial programming during severe COVID-19 that may be associated with capillary endothelial cells. However, similar patterns were not observed in larger vessels, diminishing endotheliitis and endothelial activation as key drivers of cardiovascular events during COVID-19.
Abstract 15244: Rapid Recognition and Implementation of Mechanical Circulatory Support in Rare Fulminant Lymphocytic Myocarditis
Authors: Gudiwada Mohan Chandra Vinay Bharadwaj , Saeed Izza , Kim Kathryn
Published: June 2023

Case Presentation:
A 65 year-old woman with heart failure, nonischemic cardiomyopathy, atrial fibrillation, hypertension, prior stroke presented with chest pain and shortness of breath for three days. She was ill-appearing, hypotensive and tachypneic, with troponins reaching greater than 125,000 ng/L. Initial ECG demonstrated sinus rhythm with inferior ST elevations and lateral T wave inversions, however emergent catheterization revealed angiographically normal coronary arteries. Repeat 2D echocardiography showed sharp decline to ejection fraction (EF) 5-10%. Patient subsequently developed cardiogenic shock and despite inotropes, vasopressors and intra-aortic balloon pump, she suffered ventricular fibrillation arrest requiring defibrillation. This prompted escalation with emergent veno-arterial extracorporeal membrane oxygenation. Endomyocardial biopsy findings taken at that time were consistent with lymphocytic myocarditis with negative viral panel. Her hospital course was also complicated by acute renal injury, respiratory failure requiring intubation, metabolic acidosis and shock liver. With treatment with high dose steroids and mechanical circulatory support, the patient's severely diminished EF improved to 20% and she is undergoing placement of a left ventricular assist device.

Discussion:
Fulminant lymphocytic myocarditis is a rare disease that has clinically and pathologically distinct features from subacute or acute lymphocytic myocarditis particularly in its timeline of onset and features of hemodynamic compromise. It most frequently affects young and pediatric individuals and can result in significant mortality and morbidity. This case with an older patient with severe fulminant lymphocytic myocarditis confirmed on biopsy highlights: 1) the importance of early recognition affecting survival outcome, 2) golden standard for diagnosis with endomyocardial biopsy and immunohistochemical analysis for subtype-specific evidence-based treatment, and 3) integrated medical and surgical management, including mechanical circulatory support as an essential life-saving tool.
Abstract 15247: A Novel Patient-Derived Stem Cell Model of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary to Increased Myocardial Calcium Sensitivity
Authors: Staudt David , Serrano Ricardo , Feyen Dries , Mercola Mark
Published: June 2023

Introduction:
Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described.

Hypothesis:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel
in vitro
model for investigating the molecular mechanisms underpinning this disease.

Methods:
Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq.

Results:
RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM.

Conclusions:
Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.
Abstract 15260: Role Of Purinergic Dysfunction in Worsened Outcomes for Females Undergoing Cardiac Surgery
Authors: Mahmood Eitizaz , Khan Adnan A , Qureshi Nada , Bose Ruma , Mahmood Feroze , Poulin Marie-France , Khabbaz Kamal R , Sellke Frank , robson simon , Matyal Robina
Published: June 2023

Objective:
To determine whether purinergic signaling plays a role in the adverse outcome in females presenting for cardiac surgery

Methods:
Right atrial tissue was harvested from 80 patients undergoing CABG surgery before and after and cardiopulmonary bypass (CBP). Human tissue experimentation was complemented by experiments in mice subject to a high fat diet and ovariectomy. Western blot and immunohistochemistry was carried out to interrogate the molecular derangements.

Results:
Females (n=40) had increased diastolic dysfunction (56% vs. 31%, p = .034) and length of stay (7.9 vs. 5.4 days, p = .02). We found that CD39, responsible for the enzymatic lysis of inflammatory extracellular ATP, was significantly decreased in women after CBP. Moreover, female patients demonstrated increased expression of ADORA2B, which acts as a pro-fibrotic agent responsive to adenosine as well as increased CD73, which is responsible for the lysis of adenosine monophosphate into adenosine. Finally, females demonstrated decreased adenosine deaminase, which breaks adenosine into inosine. Female patients had increased fibrosis and decreased angiogenesis (Figure 1a). Mouse models showed a similar decrease in purinergic ectonucleotidase activity as a result of ovariectomy and estrogen loss when compared to controls (Figure 1b).

Conclusions:
Purinergic signaling may serve as a key upstream mechanism responsible for the molecular derangements which underlie poorer outcomes for women following CABG surgery.
Abstract 15261: Adipor2 Sirna-Mediated Knockdown Predominantly Polarizes Towards a M1 Phenotype in THP-1 Macrophages
Authors: Gianopoulos Ioanna , Daskalopoulou Styliani S
Published: June 2023

Introduction:
Monocyte-derived macrophages (Mϕs) are the major innate immune cells in plaques, where they assume a more pro-inflammatory (M1) or anti-inflammatory (M2) Mϕ phenotype. Notably, M1 Mϕs are more abundant in unstable plaques, while M2 in stable plaques. Adiponectin receptor 1 (AdipoR1) and AdipoR2 are highly expressed in the monocyte/Mϕ lineage and largely mediate immune responses. Herein, we investigated the specific contribution of AdipoR1 and AdipoR2 on polarization towards a M1 or M2 Mϕ phenotype.

Methods:
siRNA-mediated knockdown of AdipoR1 and/or AdipoR2 was performed in THP-1 monocyte-derived Mϕs, and collected to perform, 1) qRT-PCR analyses on AdipoR1 and AdipoR2, and 2) flow cytometry analyses on M1 Mϕ markers: CD86, CD80, MHC-II, and M2 Mϕ markers: CD206, CD163.

Results:
For qRT-PCR analyses, siRNA-mediated knockdown of single AdipoR1 and AdipoR2 significantly decreased the mRNA levels of their respective receptor (p<0.01, p<0.0001), while the opposing receptor was unaffected. Double knockdown resulted in a significant decrease in both AdipoR1 and AdipoR2 mRNA levels (p<0.001, p<0.0001). For flow cytometry analyses, single AdipoR1 and double AdipoR1/R2 siRNA led to a significant decrease in ΔMFI (mean fluorescence intensity) of MHC-II (p<0.01), while a significant increase was observed in single AdipoR2 siRNA (p<0.01). Intracellular siRNA-mediated knockdown of AdipoR1 and/or AdipoR2 did not result in a significant loss of their cell surface expression, as confirmed via dot plots analyses. Lastly, single AdipoR1 and double AdipoR1/R2 siRNA exhibited decreased % MHC-II/CD86-positive cells (p<0.01, p<0.001), while single AdipoR2 siRNA increased % MHC-II/CD86-positive cells (p<0.05).

Conclusions:
Despite intracellular siRNA-mediated knockdown of AdipoR1 and/or AdipoR2, their cell surface expression remains intact. Furthermore, single AdipoR2 siRNA was associated with an increase in M1 Mϕ population (MHC-II/CD86), which is in line with our previous evidence showing decreased AdipoR2 signalling in unstable plaques. Thus, downregulation of AdipoR2 may play a role in polarization predominantly towards a M1 phenotype in THP-1 Mϕs and hence could be mechanistically relevant in the development of unstable plaques.
Abstract 15293: Predictive Value of Thyroid Hormone Levels in Patients Suffering From Cardiogenic Shock Complicating Acute Myocardial Infarction
Authors: Buerke Michael , Boettger Priyanka
Published: June 2023

Hypothesis:
Introduction. Acute critically ill patients experience a rapid decline in plasma free thyroid hormone levels (free triiodothyronine (FT3) and free levothyroxine (FT4)), with a marked elevation of reverse T3, recognized as the euthyroid sick syndrome (ESS) or low-T3 syndrome. The ESS is also often associated with depressed myocardial function, sometimes referred to as the 'stunned myocardium. The role of thyroid hormone levels in patients with cardiogenic shock complicated myocardial infarction has not been shown

Methods:
The purpose of the study was to assess the impact of thyroid hormone levels on hospital mortality in patients with infarction related cardiogenic shock. Thyroid hormone levels were measured from routine blood specimens and analyzed initial and up to 96 hours.

Results:
We identified 40 patients with infarction related cardiogenic shock treated at our university hospital. Majority of the CS-patients had on admission reduced TSH levels of 1,42 ± 0,22mU/l. Nevertheless, in-hospital mortality rate was higher in patients with lower admission TSH levels and levels over time. In addition, FT3 in CS-survivors showed a flat slope from normal levels. Non-survivor had a trend towards lower levels after 72 and 96 hours. When we analyzed for low T3 syndrome (i.e. FT3 >3,1pmol/l) we saw a 3x times higher mortality rate compared to CS patients with normal levels. In contrast, FT4 levels of non survivors were significantly elevated compared to surviving CS patients. After 96 hours both groups had similar levels. Predictors of hospital death in CS patients were low TSH levels, low T3 syndrome and elevated FT4.

Conclusions:
Thyroid hormone level on admission and over time (i.e. low TSH, low T3 and elevated FT4) are predictors of in-hospital death in patients with infarction related cardiogenic shock. Interestingly TSH stays almost stable over time whereas FT3 and FT4 declines over time. Further studies have to show if administration of thyroid hormone might be beneficial in patients with infarction related cardiogenic shock.
Abstract 15316: Associations Between Plasma Proteins With Body Composition Traits and Their Responses to Exercise Training
Authors: Clarkson William A , Barber Jacob L , Robbins Jeremy M , Cai Guoshuai , Rao Prashant , Mi Michael , Dev Prasun , Ghosh Sujoy , Katz Daniel H , Clish Clary , Bouchard Claude , Sarzynski Mark A , Gerszten Robert E
Published: June 2023

Introduction:
Although exercise training is known to alter body composition, the molecular biomarkers and mechanisms related to these changes have not been fully elucidated. The purpose of this study was to examine the associations between plasma proteins and body composition traits before and after exercise training.

Methods:
Measurements were taken before and after 20 weeks of standardized, endurance training in self-identified Black and White adults of the HERITAGE Family Study (n=647). Plasma proteins were measured using an affinity-based platform (n=4979 aptamers). 11 body composition traits were measured using underwater weighing, CT scans, and anthropometry: BMI, body surface area, fat mass, fat free mass, %fat, waist circumference, waist-to-hip ratio, body weight, and abdominal visceral, subcutaneous, and total fat. Linear mixed models were used to test the association between plasma proteins and each trait at baseline and in response to training with full covariate adjustment (
Table 1
). Significance was set to FDR<0.05.

Results:
On average, subjects were [mean and (SD)] 35 (14) years old, 33% Black, 54% female, and had BMI 26.2 (5.2) kg/m
2
. The number of significant associations between proteins and traits at baseline and in response to exercise training ranged from 645-1714 and 0-42, respectively (
Table 1
). While leptin was among the top associated proteins at both time points for almost all traits, our analysis revealed many novel associations between changes in proteins with changes in body composition. Changes in DLK-1 significantly associated with changes in 9 of 11 traits but was not associated with baseline measures.

Conclusions:
Numerous plasma proteins were associated with body composition traits at baseline, with fewer associated with trait responses to training. Notably, we identified a subset of proteins uniquely associated with exercise-induced changes in body composition traits.
Abstract 15321: MicroRNA Mir-378-3p is a Novel Regulator of Endothelial Autophagy and Function
Authors: Bu Shuhan , Nikfarjam Sepideh , Nguyen Hien Chi , Rasheed Berk , Singh Rohan , Qadura Mohammad , Frisbee Jefferson C , Singh Krishna
Published: June 2023

Introduction:
Autophagy maintains cellular homeostasis by degradation of unnecessary proteins for their recycling and reuse. MicroRNAs (miRNAs) regulate various biological processes including autophagy. MiRNA and autophagy both regulate endothelial function, however, role of miRNAs in endothelial autophagy and function is unknown.

Methods and Results:
To understand the role of miRNAs in endothelial autophagy, autophagy was genetically inhibited via ATG7 (autophagy-related gene 7) silencing in Human Umbilical Vein Endothelial Cells (HUVECs) and then a miRNA array was performed, which showed miR-378-3p as the most up-regulated miRNA. Pharmacological (via chloroquine treatment) inhibition of autophagy in HUVECs resulted in significant upregulation of miR-378a-3p. Autophagy activation via starvation in HUVECs significantly reduced miR-378a-3p expression. Next, we over-expressed miR-378a-3p (via mimic) in HUVECs and measured autophagy and endothelial function. MiR-378a-3p overexpression was associated with impaired autophagy (reduced LC3-II/LC3-I ratio), reduced proliferation, and increased migration in HUVECs. At the molecular level, miR-378a-3p overexpression was associated with reduced eNOS expression at both transcript and protein levels in HUVECs. MiR-378a-3p inhibition (via antagomir) led to reduced cell migration and upregulation of eNOS in HUVECs. In-silico study identified PDIA4 as a potential target of miR-378-3p, and our qPCR data and immunoblotting data confirmed increased and reduced PDIA4 expression in mimics and antagomir-transfected HUVECs, respectively. We then inhibited autophagy using chloroquine (50uM) and observed significantly reduced PDIA4 expression. Inhibition of PDIA4 expression via silencing inhibited autophagic flux indicated by reduced LC3-II/LC3-I in HUVECs.

Conclusions:
Our findings, for the first time, show an inverse relationship between miR-378a-3p expression and endothelial autophagy and endothelial function. PDIA4 was identified as a molecular target for miR-378a-3p in endothelial cells, which revealed PDIA4’s potential role in endothelial autophagy. Our data demonstrate that miR-378-3p regulates endothelial autophagy and function via modulating PDIA4 expression.