bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12800: Mathematical Modeling of Myocardial Transthyretin Amyloid Deposition and Clearance
Authors: Stein-Merlob Ashley F , Jin Lihua , garfinkel alan
Published: June 2023

Introduction:
In vitro
transthyretin amyloid (ATTR) fibrillation kinetics are well studied, however, the
in vivo
interplay between ATTR fibrillation and clearance causing cardiac amyloidosis (TTR-CA) is underexplored. We investigated these interactions using a mathematical model of ATTR deposition.

Methods:
We divided the mechanisms of ATTR deposition from tetramer to clearance by clusterin (an extracellular chaperone) into individual reactions (Fig. 1A) with 7 parameters. A system of ordinary differential equations (ODEs) describes the change in ATTR monomer, fibril, inhibitor, and complex deposition. Parameter values were determined using published experimental data and equilibrium analyses. We model an FDA-approved stabilizer, Tafamadis, by modifying S(t), the source term for production and dissociation of tetramers, as a step function downward at therapy initiation. Alternatively, a linear function S(t) models the hypothesis that senile TTR-CA is triggered by age-related wtTTR instability from oxidation.

Results:
The ODEs simulated a biologically meaningful model of TTR-CA. Equilibrium analyses found three phenotypes. (1) One stable, low equilibrium point representing normal myocardium (low S, high Ki). (2) Three equilibrium points, with 2 stable points (low and high) and a middle, unstable saddle point, indicating susceptibility to perturbation into a state with significant ATTR (low S/Kc2, high Ki/Kc). (3) No equilibrium points causing unbounded ATTR (high S, low Ki). In the Tafamadis model, ATTR fibril reduction was proportional to drug efficacy (Fig. 1B). Senile TTR-CA model showed rapid progression of cardiac ATTR deposition with onset dependent on slope of S (Fig. 1C).

Conclusions:
This mathematical model predicts physiologic ATTR clearance and pathological ATTR deposition with a limited number of parameters. It is a hypothesis generating model that can elucidate mechanisms of TTR-CA pathogenesis and investigate future therapies.
Abstract 12806: Attributable Mortality Benefit of Digoxin Treatment in Hypoplastic Left Heart Syndrome After the Norwood Operation
Authors: Obyrne Michael L , Song Lihai , HUANG JING , Lemley Bethan , Smith Christopher L , Tang Jie , Dori Yoav , Gillespie Matthew J , Goldberg David , Gardner Monique , Ravishankar Chitra , Rome Jonathan , Glatz Andrew C
Published: June 2023

Introduction:
Observational studies have demonstrated an association between digoxin treatment and lower interstage mortality after Norwood operation for hypoplastic left heart syndrome (HLHS), but the attributable mortality benefit has not been measureable without a clinical trial. Application of an instrumental variable can overcome confounding by indication and unmeasured confounding through pseudo-randomization.

Methods:
A multicenter retrospective cohort study of neonates with HLHS born 1/1/2007-12/31/2021, undergoing a Norwood operation at Pediatric Health Information Systems Database hospitals, and surviving >14 days post-operatively was performed evaluating the association of digoxin and 1-year transplant-free survival. Traditional multivariable logistic regression models were supplemented with instrumental variable analyses using hospital-specific 60-day likelihood of administering digoxin.

Results:
The study population included 5,148 subjects treated at 47 hospitals (63% male, 46% non-Hispanic white); 44% (n=2,184) received digoxin. Receipt of digoxin was associated with superior 1-year transplant-free survival in unadjusted analyses (85% vs. 82%, p=0.02). This persisted after adjustment for measurable confounders (OR: 0.66, p<0.001) and in an instrumental variable analysis (OR: 0.71, p=0.01, Figure).

Conclusions:
This observational study of patients with HLHS after Norwood used instrumental variable techniques to demonstrate a significant benefit in one-year transplant-free survival attributable to digoxin. In the absence of clinical trial data, this should encourage the use of digoxin in this vulnerable population..
Abstract 12821: Progressive Improvement in Left Ventricular Performance Associated With Progressive Regional Dyssynchrony
Authors: Ito Bruce R , Ervin Abbey M , Nguyen Justina P , Najera Veronica , Alvarez Cindy , Curtis Guy P
Published: June 2023

Background
: We have shown that non-excitatory epicardial stimulation (NES) increases measures of cardiac function mediated by local release of norepinephrine. In this further investigation we determined whether NES is accompanied by improved indices of left ventricular (LV) performance, reflected in PV loops and timing of aortic valve opening and closing.

Methods
: Anesthetized pigs (n=6) were instrumented with a LV high-fidelity pressure/volume conductance transducer, thoracic aortic pressure transducer, left atrial (LA)/ LV epicardial electrodes, and sonomicrometer segment length (SL) gauges placed proximal (lateral base) and distal (posterior mid LV) to the LV stimulation site. During constant LA pacing, LV pulses (0.8ms, 2-3x threshold volts) were applied during the absolute refractory period for 3 minutes (3x), before and after β-receptor blockade (BB, metoprolol). Data were analyzed at baseline, and at an estimated 30%, 60% and 100% of developed ventricular dyssynchrony (DVD) contraction pattern.

Results:
Consistent with earlier findings, NES resulted in an early shortening and relaxation pattern of the proximal SL manifest as an 80% decrease in the LVP vs. SL loop area in the absence of change in the remote segment. This was accompanied by an increase in peak systolic pressure and LV dP/dt max. Although NES did not change the area of the LVP vs. LV volume loop (stroke work) or alter the interval from LV electrical activation (R wave) to the onset of LV pressure increase, aortic valve opening occurred up to 14.1 ± 2.8 ms earlier (p <0.01) compared to baseline. The duration of an open aortic valve slightly increased (6.0 ± 3.9 ms) whereas ejection duration from valve opening to peak Pao decreased 18.2 ± 3.0 ms (p < 0.01).

Conclusion
: These findings demonstrate that NES elicits a local contractile dysynchrony resulting in an enhanced cardiac inotropic state characterized by more rapid global LV contraction with earlier aortic valve opening with no change in stroke work.
Abstract 12829: Biomimetic Cardiac Tissue Culture Model to Emulate Cardiac Physiology and Pathophysiology
Ex Vivo
Authors: Miller Jessica , Meki Moustafa H , Elnakib Ahmed , Ou Qinghui , Abouleisa Riham , Salama Abou Bakr M , Gebreil Ahmad , Lin Cindy , Abdeltawab Hisham , Khalifa Fahmi , Hill Bradford G , Abi Gerges Najah , Bolli Roberto , El-Baz Ayman , Giridharan Guruprasad , Mohamed Tamer
Published: June 2023

Introduction:
There is an urgent need for a reliable
in vitro
system to accurately replicate the cardiac physiological and pathological environment for drug testing. The limited availability of human heart tissue culture systems has led to inaccurate interpretations of cardiac-related drug effects. Our group developed a culture system for pig/human heart slices that enables functional and structural viability for 6 days using continuous electrical stimulation and enriched media. This culture system can more reliably detect cardiotoxic effects compared to hiPSC-CMs. However, by day 10, the slices undergo cardiomyocyte dedifferentiation and fibrotic remodeling making them inadequate for long-term drug testing.

Hypothesis:
To determine whether incorporating physiological mechanical, and humoral cues within the culture system can fully emulate cardiac physiology and pathophysiology in culture.

Methods and results:
We have developed a novel
c
ardiac
t
issue
c
ulture
m
odel (CTCM) that can electro-mechanically stimulate heart slices with physiological (0 to 80 mmHg) preload and afterload during each cardiac cycle. After 12 days in culture, this approach alone partially improved the viability of heart slices but did not maintain the structural integrity. Therefore, following a small molecule screening, we found that incorporating 100 nM tri-iodothyronine (T3) and 1 μM dexamethasone (Dex) into our culture media preserved the structural integrity of the slices for 12 days. When combined with T3/Dex, the CTCM system fully maintained the transcriptional profile, viability, metabolic activity, and structural integrity for 12 days at the same levels as fresh heart tissue. Furthermore, to test the ability of the CTCM to emulate cardiac hypertrophy, increasing the peak pressure to 140 mmHg resulted in induced cardiac hypertrophy within 6 days in culture as indicated by a 3-fold increase in NT-ProBNP release, increased NFATC4 and P-ERK expression, and increased cardiomyocyte cross-sectional area.

Conclusions:
This new CTCM heart slice culture system incorporating physiological electromechanical and humoral cues can emulate cardiac physiology and pathophysiology in culture, which could be used for drug screening for new therapeutics and cardiotoxins.
Abstract 12841: Overexpression of Scarna20 Promotes Small Nuclear RNA Pseudouridylation and Improves Cardiomyogenesis
Authors: Sigamani Vinoth , Perales Selene G , RAJASINGH SHEEJA , Johnson Rajasingh
Published: June 2023

Introduction:
Non-coding RNAs, particularly small Cajal body-associated RNAs (scaRNAs), play an important role in alternative splicing and maturation of mRNAs through pseudouridylatory modification. Our small non-coding RNA sequencing analysis has identified that scaRNA20 plays a major role in cardiomyocyte differentiation. In this study, we aim to elucidate the role of scaRNA20 during cardiac differentiation using
in vitro
induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMC) subjected to 3% hypoxic conditions.

Hypothesis:
Overexpression (OE) of scaRNA20 in iPSCs leads to enhanced cardiomyogenesis and increases the endurance properties of cardiomyocytes by maintaining contractility under hypoxic conditions.

Methods and results:
We have used OE and knockdown (KD) assays to delineate the role of scaRNA20 during the process of iPSC to iCMC differentiation. The video recordings of scaRNA20-OE-iCMCs and scaRNA20-KD-iCMC contractilities were measured by a novel Particle Image Velocimetry (PIV) method. Our results show that the contractility was impaired in control iCMCs whereas in scaRNA20-OE-iCMCs it was well-maintained under the hypoxic conditions. In contrast, scaRNA20-KD-iCMCs resulted in poor differentiation, they were non-functional and had an impaired contractility. Furthermore, we investigated the pseudouridylation levels of spliceosomal RNA U12 which is a direct target for scaRNA20. We found an increased level of Ψ
28
in scaRNA20-OE iCMCs
(Figure A-D)
. In addition, the scaRNA20 overexpression in iCMCs resulted in the upregulation of DKC1, NHP2, and NOP10 and downregulation of GAR1, COIL, and WRAP53 and these effects regulate the activation of pTP53 and STAT3 and thus activating cardiac genes.

Conclusion:
Taken together, our results show for the first time that modulation of iCMCs with scaRNA20 helps maintain the endurance properties of cardiomyocytes while under hypoxic conditions, and it also improves cardiomyogenesis.
Abstract 12870: Absence of LDL Measurement in Secondary Prevention is Associated With Increased Subsequent Major Adverse Clinical Event (MACE) That is Only Partially Mitigated by Statin Use
Authors: Knowlton Kirk U , May Heidi T , Bair Tami L , Anderson Jeffrey L , Lappe Donald L , Muhlestein Joseph B
Published: June 2023

Introduction:
There has been considerable discussion regarding the value of follow-up LDL-C measurements in secondary prevention of major adverse cardiac events (MACE). We therefore set out to determine in a large healthcare system whether measurement of LDL-C after an ASCVD event was associated with a difference in MACE during follow-up and whether differences in outcomes could be attributed to differences in statin use.

Methods:
The Intermountain Enterprise Data Warehouse was searched to identify all adults with a first encounter for ASCVD-including coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD)—between January 1, 1995 and December 31, 2016 who survived the index event and were followed for ≥3 years or until death.

Results:
Patients (N=68,411) had an average age of 66±14 years; 65% were men; 70.3%, 21.0%, and 8.6% entered with CAD, CVD, and PAD, respectively. A statin was prescribed to 52% of patients during follow-up. A total of 33,698 (49%) did not have and 34,713 (51%) did have a follow-up LDL-C test prior to a subsequent MACE (death, MI, CVA, and revascularization) or end of follow-up. By 3 years, MACE occurred in 14,835 (37.4%) vs. 5,770 (20.1%) of those without vs. with an LDL-C measurement, respectively (Figure top). The multivariable hazard ratio for 3 year MACE based on measuring LDL-C was 0.47. The increased MACE rate associated with not measuring LDL-C was partially mitigated by statin use (Figure bottom). Only 44.7% vs. 58.9% of patients without vs. with LDL-C measurement were taking statins.

Conclusion:
These data indicate that there is a significant and clinically meaningful difference in MACE based on a follow-up measurement of LDL-C. Statin administration partially, but not completely mitigated the increased MACE rate. While these results are limited in that they are from a retrospective registry, they indicate that LDL-C should be measured, and statin should be administered after an initial ASCVD event.
Abstract 12877: Investigation of the Role of Fgf23 in the Pathogenesis of Post-Splenectomy Cardiovascular Dysfunction
Authors: Wang Ling , Satoh Taiju , Sinchar Derek , Bachman Timothy , Yang Minying , Baust jeffrey J , Gladwin Mark T , Li Hongshuai
Published: June 2023

Introduction:
Splenectomy is a relatively common surgical procedure in hematologic disorders, such as thalassemia, to improve anemia. However, splenectomy is clinically indicated as a strong risk factor for the development of post-splenectomy cardiovascular dysfunction. The underlying mechanisms have not been well established. We have found elevated levels of circulating FGF23 in thalassemia mice. As a hormone mainly expressed by osteocytes in bone, FGF23 has been shown to be an independent marker for cardiovascular risk in various patient populations. In this study we sought to investigate the role of FGF23 in the pathogenesis of post-splenectomy cardiovascular dysfunction.

Methods:
Splenectomy was performed in thalassemia (

Hbb
th-3

) mice at 4 weeks of age and cardiovascular functions were evaluated at 10 weeks post-splenectomy. Right ventricular maximum systolic pressure (RVSP) was measured using a closed chest right heart catheterization approach. Cardiac structure and functions were evaluated using echocardiography. Realtime RT-PCR and immunostaining were used to determine FGF23 expression in mouse tissues. Hepatocyte specific FGF23 KO thalassemia mice were generated by cross breeding albumin-Cre, Flox-Fgf23 and thalassemia mice.

Results:
Using a thalassemia mouse model (

Hbb
th-3

), we found that

Hbb
th-3

mice with surgical splenectomy developed significant cardiovascular dysfunction including biventricular cardiac hypertrophy, impaired diastolic function as well as pulmonary hypertension. We also found circulating levels of intact FGF23 were dramatically elevated in splenectomised

Hbb
th-3

mice, along with significantly upregulated FGF23 expression in liver and bone tissues. However, FGF23 levels in plasma were not normalized in hepatocyte specific FGF23 KO mice, suggesting bone-derived FGF23 is most likely the major source account for elevated FGF23 in circulation.

Conclusions:
Our findings suggest bone-derived FGF23 may contribute to the development of post-splenectomy cardiovascular dysfunction in thalassemia. The role of FGF23 in post-splenectomy pathogenesis will be further investigated using global FGF23 KO and osteocyte specific FGF23 KO mouse models.
Abstract 12896: Case of Probable Takutsubo's Cardiomyopathy Post Intravenous Immunoglobulin Infusion for Neuromyopathy Syndrome
Authors: Ayyalu Tanesh K , Goyfman Michael
Published: June 2023

Introduction:
 Takotsubo’s Cardiomyopathy (TCM) is a diagnosis of exclusion recognized by regional left ventricle (LV) dysfunction and absent coronary artery disease. There are isolated reports of patients with autoimmune conditions developing TCM post intravenous immunoglobulin (IVIG). IVIG is a plasma product which inactivates microbial antigens and downregulates certain cytokines, but its cardiac effects are varied. Our case describes a female with progressive neuromyopathy who developed cardiomyopathy post IVIG infusion.  

Case:
 A 68 year old female, with type 2 diabetes, hypertension, stroke, and neuromyopathy presented with worsening dysarthria and gait issues for 2 years. Examination revealed multiple neurological deficits, and vital signs showed pulse of 105 with blood pressure of 101/75 mmHg. Initial electrocardiogram (EKG) showed sinus tachycardia and CT angiogram of head was unremarkable. She had a negative cardiac catheterization 2 years ago and a normal echocardiogram 6 months ago. IVIG 400 mg/kg daily for 5 days was started for neuromyopathy flare. She had chest pain on infusion day 4. EKG showed ST elevation in leads V2-V4, and labs revealed troponin I of 0.96 ng/ml with proBNP of 7583 pg/mL. Echo showed LV akinesis with preserved basal segmental function suggestive of TCM. Carvedilol and losartan were started. Further ischemic work up was not done as she died from respiratory failure.  

Discussion:
 IVIG is linked to thromboembolic events including strokes and myocardial infarction (MI), but TCM is rare. Risk factors include high dose therapy (>1g/kg), coronary artery disease, prior MI, smoking, diabetes, hypertension, autoimmune conditions, or hyperviscosity states. Our patient had multiple risk factors for MI post infusion including age, gender, and comorbidities. Her assessment is limited by incomplete ischemic workup. IVIG may have negative cardiac effects secondary to vasoconstrictive cytokines, arterial spasm, or increased blood viscosity, but is confounded by other factors in this case.  

Conclusions:
IVIG has poorly described cardiac effects including possible induction of TCM. Further trials monitoring cardiac outcomes post IVIG stratified by dosage and risk would improve patient selection and education.
Abstract 12917: Reproducibility of Use by Physicians and Patients of a Smart Stethoscope for Artificial-Intelligence Enhanced Diagnosis of Heart Failure
Authors: Wickramathilaka Akila , Kelshiker Mihir A , Griffin Jake , Gandhi Manisha , Petri Camille F , Almonte Melanie T , Bachtiger Patrik , Peters Nicholas S
Published: June 2023

Introduction:
Early detection of heart failure (HF) is a global health system priority. An artificial intelligence-enhanced stethoscope (‘Eko DUO’), is capable of recording and analysing a single-lead ECG to detect HF with reduced left ventricular ejection fraction (LVEF≤40%) after only 15 seconds of apposition to the chest. Given this simplicity, patient-administered remote HF diagnosis and screening is feasible if performance and reproducibility of use of the Eko DUO is adequate.

Hypothesis:
We tested hypotheses that:

1. Eko DUO predictions for LVEF≤40% have good intra- and inter- operator reproducibility (intra-class correlation coefficient > 0.75) for both patient and clinician deployment.

2. Eko DUO performance for detection of LVEF≤40% is comparable between patients and clinicians

Methods:
98 hospital inpatients undergoing echocardiography at Imperial College Healthcare NHS Trust, UK, performed self-examination with the Eko DUO, using instructions to take three recordings from the left parasternal 2nd intercostal position. A clinician then repeated three recordings. The intra-class correlation coefficient was calculated using the raw numerical artificial intelligence predictions for LVEF≤40%. Performance for detection of LVEF≤40% was measured by calculating the area under the receiver-operating characteristic curves (AUC) using a reference standard of echocardiography-derived percentage LVEF.

Results:
There was good intra-operator reproducibility for both patients (ICC = 0.817) and for clinicians (ICC = 0.888), and good inter-operator reproducibility between patient and clinicians (ICC = 0.887). The performance of the Eko DUO was comparable between patients and clinicians (AUC = 0.887 vs. AUC = 0.800, respectively).

Conclusions:
The Eko DUO predictions for LVEF≤40% have good intra- and inter-operator reproducibility between patients and clinicians.
Abstract 12919: Stress Induced Cardiomyopathy After the Covid-19 Vaccine
Authors: Pakanati Keerthana , Nguyen John , Stoebner Richard
Published: June 2023

Introduction:
The SARS-CoV-2 virus has potential to cause acute and long-term cardiac effects. The vaccines were developed to prevent severe illness, but there are concerns about vaccine related side effects. Specific to the heart there have been case reports of mRNA vaccine related cardiomyopathies, particularly myocarditis. We present a case of a patient with presumptive stress induced cardiomyopathy in the setting of recent Covid-19 mRNA vaccination.
Case Presentation:
A 93-year-old female with a past medical history of hypertension presented with worsening shortness of breath and bilateral lower extremity edema. She received her second dose of the Covid-19 mRNA vaccine five days prior to presentation. She had no history of heart disease, was a nonsmoker, and denied alcohol or drug use. In the ED she was noted to be fluid-overloaded, and her CT chest showed minimal coronary calcification and bilateral pleural effusions. She was admitted for heart failure exacerbation and started on IV furosemide. Her transthoracic echocardiogram showed an ejection fraction of 40-45%. The pattern of left ventricular dysfunction was consistent with stress induced cardiomyopathy with apical akinesis and basal sparing of the left ventricular wall segments. Cardiology was consulted and recommended management with diuretics and beta blocker. She had a diuresis of 5 liters during her hospitalization. At clinic follow-up, dyspnea had improved, and her peripheral edema had resolved. Repeat echocardiogram showed recovery of left ventricular ejection fraction to 61% by Simpsons biplane technique with no regional wall motion abnormalities. Further cardiac assessment to evaluate for obstructive coronary artery disease and myocarditis was discussed and offered to the patient but was declined due to her positive response to conservative management.

Discussion:
The precise etiology of stress induced cardiomyopathy is unknown, but it is thought to be secondary to the sudden release of stress hormones. There are isolated reports of stress induced cardiomyopathy associated with Covid-19 vaccination, but the potential mechanism is unclear. An improved understanding of the potential effects of mRNA vaccines may help guide decisions regarding future booster vaccinations.
Abstract 12926: Senescent CD8 T Cells are Enriched in Atherosclerotic Plaques From Patients With Type 2 Diabetes and Their Circulating Levels Are Normalized by Intensive Lipid Lowering
Authors: Eberhardt Natalia , Kaur Ravneet , Gildea Michael , Das Dayasagar , Amadori Letizia , Fernandez Dawn , Shamailova Roza , sajja swathy , Jindal Manila , Rockman Caron , Maldonado Thomas , Fisher Edward , Goldberg Ira J , Berger Jeffrey , Giannarelli Chiara
Published: June 2023

Introduction:
Senescence is a key driver of age-related chronic inflammatory diseases including type 2 diabetes (T2D). Senescent T cells lose their ability to control tissue homeostasis and present aberrant cytokine and cytotoxic responses that ultimately cause tissue damage. Atherosclerotic plaques from T2D present more severe pathology than patients with no diabetes (ND) and circulating senescent CD8 T cells are increased in T2D and associated with myocardial infarction. However, whether senescent CD8 T cells accumulate in atherosclerotic plaques of T2D patients is unknown.

Hypothesis:
Senescent T cells infiltrate atherosclerotic plaques and contribute to the aggravated cardiovascular risk in T2D.

Methods:
We performed unbiased scRNA-seq analysis (75,049 total cells) of plaques from T2D (n=12) and ND patients (n=10) enrolled in the Athero-In Study. Circulating immune cells from T2D (n=16) and ND (n=6) patients enrolled in the CHORD study were analyzed using mass cytometry (CyTOF) before and after lipid lowering treatment.

Results:
We found a cluster of CD8 T cells expressing a senescence gene signature (
B3GAT1, KLRG1, KLRF1),
as well as proinflammatory (
IFNG, TNF, CCL4, CCL5
) and cytotoxic (
GZMB, PRF1, GNLY
) genes. Plaque senescent CD8 T cells showed a terminally differentiated effector memory phenotype (TEMRA) with high expression of
CX3CR1
and low expression of lymphoid-homing genes (
SELL, CCR7)
. CyTOF analysis revealed that circulating senescent CD8+ CD28- CD57+ T cells were increased in T2D compared to ND patients. Treatment with PCSK9 inhibitor plus statin/ezetimibe, which reduced LDL levels by >70% at 4 weeks, normalized senescent CD8 T cell frequency in T2D patients to the levels of ND subjects at baseline. No changes were observed in cells from cholesterol-reduced ND patients.

Conclusions:
Our results show that senescent CD8+ T cells are enriched in atherosclerotic plaques and blood of T2D patients. The observation that acute lipid lowering normalized circulating senescent CD8 T cells in T2D patients indicates that T cell senescence can be improved by more aggressive lipid control in high risk T2D subjects. Further analyses are needed to understand how T cell senescence contributes to atherosclerosis and impaired regression in T2D.
Abstract 12934: Refractory Hypercholesterolemia Induced by Treatment of Adrenocortical Carcinoma Demonstrates a Significant Challenge in Cardiovascular Disease Risk Management
Authors: Wilbur Jameson G , James Amy , Wyne Kathleen L
Published: June 2023

Introduction:
Hypercholesterolemia is a significant modifiable risk factor for cardiovascular disease (CVD). Prompt management of high-risk patients presenting with this condition is paramount, particularly for those with other comorbid conditions.

Case Description:
A 37-year-old female with long-standing well-controlled type 1 diabetes (over 30 years), metabolic syndrome, and mildly elevated LDL (128-138 mg/dL) on maximally tolerated statin therapy was diagnosed with adrenocortical carcinoma. She continued statin therapy through multiple different anti-tumor protocols including traditional agents, immunotherapy and mitotane. She returned to diabetes clinic twenty months after the diagnosis, after starting a new anti-tumor protocol following progression of disease despite three different protocols, where lipid profile was drawn showing severe hypercholesterolemia with elevations in total cholesterol (489 mg/dL) and LDL-c (388 mg/dL). Given her risk for CVD, intensive lipid lowering therapy was started by our multidisciplinary treatment team. LDL-c did not attain goal on a PCSK9-inhibitor, nor did it improve with testing a high dose of a different statin. Finally, after testing multiple different agents and combinations over the subsequent twelve months, the LDL-c has achieved goal of < 100 mg/dL on a multi-drug regimen consisting of a PCSK9-inhibitor, statin, ezetimibe, and bempedoic acid. The LDL-c has now been maintained within goal range for six months.

Discussion:
This case illustrates the potential for severe refractory hypercholesterolemia induced by the treatment of adrenocortical carcinoma. Little literature exists guiding therapy for these patients. The present case suggests management may require multimodal therapy targeting several mechanisms of lipid metabolism, an escalation from traditional therapy. As survival outcomes for patients with many cancers improve with advances in treatment, management of risk factors for CVD is tantamount for reducing long-term morbidity and mortality. While routine lipid monitoring is not typically performed during cancer treatment, it may well be beneficial. Further research optimizing screening and treatment is warranted.
Abstract 13000: The Effect of Flow Dynamics on the Neotissue Formation of 3D Printed Tissue Engineered Vascular Graft
Authors: Hayashi Hidenori , Matsushita Hiroshi , Watanabe Tatsuya , Lee Nora , Dunn Tyler , Nurminsky Katherine , Mass Paige , Cleveland Vincent , Contento Jacqueline , Nelson Kevin , Huddle Joey , Rodgers Daniel , Kawaji Keigo , Johnson Jed , Olivieri Laura , Krieger Axel , Hibino Narutoshi
Published: June 2023

Introduction:
Complex vascular reconstruction such as that of the right ventricle to pulmonary artery (RVPA) and the aortic arch remains challenging due to the various 3D geometry of each patient. Tissue-engineered vascular grafts (TEVG) possess not only excellent antithrombotic and anti-infective properties but also the ability to grow as the patient matures. 3D printed patient-specific TEVG can maintain optimal hemodynamics with the growth of the patient and may improve surgical outcomes. We applied our unique 3D printing technology to create patient-specific TEVG for RVPA and the aortic arch.

Methods:
We acquired MRI and 4-dimensional flow data for the native anatomy of pigs (n=8) to design a patient-specific TEVG of the pulmonary artery (n=5) and the aortic arch (n=3) 4 weeks prior to surgery. The optimal shape of the branched vascular graft (n=8) was designed using a computer-aided design informed by computational flow dynamics analysis. We manufactured and implanted the grafts into the RVPA or aortic arch in the porcine model. The grafts were explanted after surgery at 8 - 12 weeks for evaluation. Pre- and post-op implant flow dynamics data in MRI and histology were analyzed.

Results:
The local neointimal thickness of TEVG in histology and the corresponding area of wall shear stress in 4D MRI were measured. Low wall shear stress, an aspect of MRI flow analysis, demonstrated a significant correlation with decreased neointimal thickness through histology (R2=0.65, P=0.016), which suggested optimal shape and design is important for appropriate neotissue formation.

Conclusions:
Our 3D printed custom designed TEVG demonstrated optimal anatomical fit maintaining ideal flow dynamics can attenuate neointimal hyperplasia and appropriate neovessel formation.
Abstract 13009: Time to Implantable Cardioverter Defibrillator in Patients With Left Ventricular Ejection Fraction ≤ 35%
Authors: Vajta Gomez Jackeline P , Elbey Mehmet , Borz-Baba Carolina I , Gnanaraj Joseph
Published: June 2023

Background:
Implantable cardioverter-defibrillators (ICDs) are endorsed by the current American Heart Association (AHA) Guidelines as the cornerstone in the primary prevention of mortality in patients with reduced ejection fraction (EF) (≤35%). The timing for ICD therapy in non-ischemic cardiomyopathy (NICM) is not specified in the current guidelines. The objective of this study was to determine the timing for ICD insertion for patients with NICM versus ICM in the real-world population.

Methods:
Retrospective design study of patients with ICDs implantation from 2019 to 2022 at our community hospital. Data was obtained via the Device Implant Registry. All eligible participants had confirmed diagnosis of ICM and NICM on chart review; while confirmed EF≤35% on echocardiography. Categorical predictors and clinical outcomes were analyzed using Pearson’s chi-square test or Fisher’s exact test. Quantitative predictors and clinical outcomes were analyzed using Student's t-test or the Wilcoxon rank sum test.

Results:
Our cohort included 62 patients undergoing ICD placement for primary prevention. There was no statistical significance between patients based on age, sex, race, and EF. Average time to ICD placement was 134 days for patients with ICM and 274 days for patients with NICM, a difference that favoured NICM;
p
=0.009 (
p
<0.05). In the majority of patients, 64.5%, ICD implantation was deferred for at least 90 days compared to 35.5% patients who had an ICD placed by 90 days;
p
=0.001 (
p
<0.05). The mortality in our study was 13% over a median of 2 years, with a predominance of ICM as compared to NICM, 75% versus 25%, respectably. Logistics regression demonstrated that timing to ICD implantation was not an independent variable of mortality. The mean overall survival was 274.4 days (SD +/- 50) in NICM compared to 134.3 days (SD +/- 21) in the ICM group,
p
=0.007 (
p
<0.05).

Conclusions:
In a real-world population, time to ICD implantation was statistically different in ICM compared to NICM. ICM remains a significant risk of all-cause mortality despite the progress made in both medical and procedural treatments. Further studies are necessary to determine the appropriate time to ICD implantation in patients with NICM and reduced EF.
Abstract 13030: Non-Exercise Machine Learning Model for Maximal Oxygen Uptake Prediction in National Population Surveys
Authors: Liu Yuntian , Huang Chenxi , Mortazavi Bobak J , Khera Rohan , Krumholz Harlan M , Lu Yuan
Published: June 2023

Introduction:
Maximal oxygen uptake (VO
2
max), an indicator of cardiorespiratory fitness (CRF) requires exercise testing and, as a result, is rarely ascertained in large-scale population-based studies. There are many non-exercise algorithms that can estimate VO
2
max, but they are limited by their non-representative study population, lack of predictors, and the insufficient predictive power for the type of model chosen. In this study, we aim to improve the non-exercise algorithms using machine learning (ML) methods and data from U.S. national population surveys.

Methods:
We used the 1999-2004 data from the National Health and Nutrition Examination Survey (NHANES) because it included exercise testing to measure VO
2
max. Based on the literature review, predictors were identified from demographic, interview, examination, and laboratory data. The study population was split into a training set (80%) and a testing set (20%) for model development and validation. We built the improved model using Light Gradient Boosting Machine (LightGBM) for its outstanding performance and built-in functionality for handling missingness. The model was trained by optimizing Root-Mean Squared Error (RMSE) and using 5-fold cross-validation. Existing non-exercise algorithms for comparison were applied to the testing set.

Results:
Among the 5,668 participants included, the mean age was 32.5 and 49.9% were women. 40 predictors in total were selected for the final feature set. The fitted LightGBM model achieved an RMSE of 8.43 ml/kg/min (95% CI: 7.64 -9.19) on the testing set, significantly reducing the error by 14% (P <0.05) compared with the best existing non-exercise algorithms that could be cross-validated in NHANES (Table1).

Conclusion:
In conclusion, the extended non-exercise ML model in this study can provide a more accurate prediction of VO
2
max for NHANES participants, and those with similar data, than the existing non-exercise algorithms.
Abstract 13037: RAS Inhibition is Associated With Higher Risk of 60-Day COVID-19-Induced Myocarditis
Authors: VAELI ZADEH ALI , Wong Alan , Zachariah Ashvin , Collado Elias , Larned Joshua
Published: June 2023

Background:
COVID-19 related myocarditis (MC) can manifest with no symptoms, chest pain, life-threatening arrhythmia with hemodynamic instability, or new heart failure. Evidence suggests that RAS inhibition may be beneficial for some patients during COVID-19 infection; however, the effect of these drugs on risk of developing COVID-19-induced MC is not well characterized.

Methods:
Using ICD-10 codes, a cohort of patients admitted between March-October 2020 with the primary diagnosis of COVID-19 was identified from the PearlDiver database (PearlDiver Technologies, Fort Wayne, IN). Use of RAS inhibitors over the past 6 months was used to split the cohort into two case-control matched groups based on age, gender, and Elixhauser Comorbidity Index. Using the same matching criteria, the RAS group was divided into ACEi and ARB groups. Records of all groups were reviewed to determine the incidence of MC, 60 days after admission. We used Pearson's chi-squared test to compare the MC frequencies. Kaplan-Meier plot and log-rank test were used to compare time-to-event between groups. The strength of association was reported as Risk Ratios (RR) and 95% CI. A p-value <0.05 was deemed significant.

Results:
Patients using RAS inhibitors had a higher risk of 60-day MC than those who did not (RR = 3.71, 95% CI = 1.61-8.58, p = 0.0017). The p-value of the log-rank test for the 60-day Kaplan-Meier analysis was 0.0006. There was no significant risk difference between ACEi and ARB groups (RR = 0.4, 95% CI = 0.12-1.27, p = 0.18). (Figure 1)

Discussion:
Our study showed a significant increased risk of 60-day MC in COVID-19 patients taking RAS inhibitors, with no difference between ACEi and ARBs. A plausible explanation is that the RAS inhibition leads to cardiomyocyte's ACE2 overexpression, thereby permitting SARS-CoV-2's cellular entry. This interpretation is limited due to the inherent bias associated with retrospective research and the paucity of additional evidence.
Abstract 13047: Are Clinicians Using All Available Strategies to Achieve Guideline-Recommended Lipid Lowering?
Authors: Navar Ann M , Gupta Anand , Gillard Kristin K , Israel Marc , Peterson Eric D
Published: June 2023

Introduction:
Despite their safety, efficacy, and low-cost, statins are under-utilized in both primary and secondary prevention populations. Multiple strategies are available to facilitate lipid lowering in those who report statin intolerance including using alternate statins, low-intensity or alternate-day statin dose schedules, or using non-statin lipid lowering therapies. However, the degree to which these alternative strategies are tried in community practice is unknown.

Methods:
We evaluated prior statin use among n=731,895 persons who met guideline recommendations for statin therapy between 2017-2018 in Cerner RealWorldData, an electronic health record (EHR)-based dataset from 94 health systems. Medication data available included all prescriptions generated from the EHR and self-reported medications recorded in the EHR (median of 4 years of medication data for each subject).

Results:
Among 731,895 individuals who met guideline recommendations for statin therapy, 278,434 (38.0%) were not on a statin. Of those not on a statin, only 20.1% (n=55,875) had any evidence of prior statin therapy, and 12.3% had documentation of a statin allergy. Among prior statin users,most had only tried one (68.0%) or two (23.5%) statins before stopping all together. Only 1.3% of former statin users had been prescribed a statin at less than daily frequency, while 22.6% had been prescribed a low-intensity statin at some point in the past. Utilization of non-statin lipid lowering therapy was also rare: Among those not on a statin, only 2.6% were on ezetimibe, 4.4% were taking a fibrate, 1.5% a bile acid sequestrant, 1.6% niacin, and 0.3% were taking on a PCSK9 inhibitor.

Conclusion:
Across 94 health systems, almost 40% of persons recommended for statin therapy for primary or secondary prevention were not on a statin, the vast majority of which had no evidence of prior statin utilization. Of those who had tried a statin in the past but discontinued therapy, very few appeared to have attempted a re-challenge with a different statin, tried alternative dosing strategies to improve tolerability, or initiated non-statin lipid lowering therapy.
Abstract 13073: Antisense Transcripts Regulate Titin Alternative Splicing and Sarcomere Function in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Celik Selvi , Hyrefelt Ludvig , Czuba Tomasz , Andre Oscar , Lindquist Lovisa , Grossi Mario , Nordenfelt Pontus , Smith Gustav , Gidlof Olof
Published: June 2023

The giant protein Titin is an essential structural component of the sarcomere and a key determinant of passive tension during diastole. Titin tension is regulated by alternative splicing within the spring-like domains in the I-band region of
TTN
pre-mRNA. The cardiac RNA-binding protein RBM20 has been shown to promote
TTN
exon skipping during splicing, but additional factors are likely involved. We hypothesized that a natural antisense transcript in the
TTN
locus (
TTN-AS1
) could regulate
TTN
splicing in
cis
through recruitment of spliceosome components. Through single nuclei RNA-Seq and RNA fluorescence in situ hybridization (ISH) on human cardiac tissue and iPS-derived cardiomyocytes (iPS-CM), we showed that the expression of
TTN-AS1
was restricted to cardiomyocyte nuclei. The percent spliced in (PSI) of each
TTN
exon was calculated based on RNA-Seq data from iPS-CM (n=3) and 26 exons (all in the I-band region) that are normally spliced out were included to a significantly higher extent (adjusted p<0.05) upon siRNA-mediated
TTN-AS1
knock down. Reduced exon skipping from
TTN
exon 50 was confirmed with exon-junction spanning qPCR probes (p<0.05, n=3). Similar effects on splicing were seen in cells where
RBM20
had been knocked down. The consequences of
TTN-AS1
knock down on cardiomyocyte contractile function was assessed using sarcomere tracking. Transgenic expression of
ACTN2-GFP
was used to visualize z-disks in iPS-CM, sarcomeres (n=14,636) were recorded during contractions using wide-field epifluorescence microscopy and analyzed using Sarc-Graph software. The analysis revealed that in cells where
TTN-AS1
had been knocked down, sarcomere length and fractional shortening, as well as contraction and relaxation time were increased (all p<0.001). Again, similar effects were seen in iPS-CM where
RBM20
had been knocked down. We observed co-localization of
TTN-AS1
and RBM20 protein during active TTN splicing in iPS-CM nuclei using multiplex RNA ISH and immunofluorescence and confirmed interaction between
TTN-AS1
and RBM20 using RNA Immunoprecipitation and qPCR. In conclusion, we show that
TTN-AS1
can affect cardiomyocyte contractile properties and sarcomere dynamics through regulation of
TTN
alternative splicing.
Abstract 13093: Global Longitudinal Strain Prediction of Cardiac Dysfunction in Hematopoietic Stem Cell Transplant Patients
Authors: Lin Wei-wen , Teng Chieh-Lin, Jerry , Liu Chia-CHi , Lee Wen-Lieng
Published: June 2023

Introduction and Hypothesis:
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for hematological malignancies, but patients undergoing HSCT are at increased risk of cardiovascular events and death. Global longitudinal strain (GLS) is more sensitive than left ventricular ejection fraction (LVEF) to identify subclinical LV dysfunction. Early heart failure guideline-directed medical therapy (GDMT) may improve heart function and symptoms in these patients.

Methods:
Transthoracic echocardiography with speckle tracking was performed every 3 months for 9 months before and after BMT (Figure 1A), with GLS and LVEF as markers of systolic function and E/e' as markers of diastolic function, troponin I, NT-ProBNP and D-dimer as markers of cardiac insufficiency. Patients with a 10% reduction in GLS or a 15% reduction in LVEF from baseline were defined as LV dysfunction and GDMT were prescribed.

Results:
A total of 27acute myeloid leukemia and 5 acute lymphoblastic leukemia received high dose cyclophosphamide before HSCT, 2 patients developed minimal pericardial effusion without tamponade, 2 patients expired during transplantation. The mean GLS before HSCT was -16.8±0.75%, which was significantly reduced to -15.11±0.86% (p=0.026) after 3 months (Figure 1B). After GDMT, GLS improved to -18.86±1.6% 9 months after HSCT. No significant changes in LVEF, E/e' and serum biomarkers during follow-up

Conclusions:
Our results further support an increased risk of subclinical myocardial dysfunction in patients with hematological malignancies on HSCT. In these patients, GLS may be an earlier noninvasive marker than LVEF, ECG, or serum biomarkers. Early heart failure GDMT may improve heart function once GLS is reduced.
Abstract 13098: CircRNA-miRNA-mRNA Networks Regulate Endothelial Function in Ischemic Heart Disease
Authors: Anwar Maryam , Sarkar Moumita , Chamorro-Jorganes Aranzazu , Ford Kerrie , angelini gianni , Punjabi Prakash , Emanueli Costanza
Published: June 2023

Introduction:
Ischemic heart disease (IHD) is characterized by reduced blood supply to the myocardium and is aggravated by Type 2 Diabetes Mellitus (T2DM). Most of the RNA produced by the human genome is “non-coding” in potential and involved in regulatory processes. These include circular RNAs (circRNAs) and microRNAs (miRNAs). miRNAs bind to the 3’UTR region of their target genes and repress their expression post-transcriptionally. CircRNAs lack free ends which gives them increased stability and makes them good candidates for diagnostic biomarkers and therapeutic interventions. CircRNAs bind miRNAs via a process called “sponging” that prevents the miRNAs from binding to their target genes. This study investigates the regulatory role of circRNAs in IHD and its effect on endothelial cell (EC) function.

Methods and Results:
We have generated bulk RNA-seq data on whole transcriptome and small RNA using heart left ventricle (LV) biopsies of 3 groups of cardiac surgery patients: 1) and 2) suffering from IHD) with/without T2DM and 3) non-ischemic controls. Bioinformatics analysis of this data has identified significant differentially expressed circRNAs, miRNAs, and mRNAs in IHD and IHD + T2DM patients. Using available databases and tools, we have predicted “sponging associations” between circRNAs and miRNAs as well as targets of sponged miRNAs producing circRNA-miRNA-mRNA networks. Since fundamental changes in IHD include a decline in EC function, we extracted all components of the networks expressed in ECs. Of note is circNPHP1, which is upregulated in IHD + T2DM patients and in human microvascular endothelial cells (HMVECs) under hypoxic and hypoxic + high glucose (HG) conditions. Furthermore, knockdown of circNPHP1 in HMVECs leads to a significant reduction of proliferation and angiogenesis under hypoxic and hypoxic + HG conditions. The downstream miRNA and mRNA connections of circNPHP1 are currently under investigation.

Conclusion:
circNPHP1 expression shows concordance in clinical samples and cultured cells in response to perturbation (ischemia/hypoxia and T2DM/HG). It also seems to be playing a role in EC function restoration under these conditions and is therefore promising for further investigation into its therapeutic target potential.