bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14933: Beta1-Adrenergic Receptor Polymorphisms Modulate Receptor Processing and Function
Authors: Tuhkanen Hanna E , Lackman Jarkko J , Goth Christoffer K , Haasiomaki Ilona , Clausen Henrik , Magga Johanna , Kerkela Risto , Schjoldager Katrine , Petaja-Repo Ulla E
Published: June 2023

The beta1-adrenergic receptor (beta1AR) is a G protein-coupled receptor that modulates the sympathetic activation of the heart. The extracellular N-terminal domain of the beta1AR, that undergoes extensive post-translational modifications, is generally overlooked as a domain influencing receptor signaling and regulation. Previously, we showed that the N-terminal domain is cleaved in an activation dependent manner, and more recently, we demonstrated that O-glycosylation inhibits the N-terminal cleavage and modulates signaling of the receptor. This suggests that processing of the N-terminal domain has a complex role in the regulation of beta1AR function. Here, we investigated the three human beta1AR (hbeta1AR) N-terminal single-nucleotide polymorphisms (SNPs) that reside close to the previously identified cleavage and O-glycosylation sites. These SNPs, S49G, R31Q and A29T, have allele frequencies of ~15%, <1% and <1%, respectively. The aim was to investigate if these SNPs can modulate the O-glycosylation -mediated receptor regulation. We studied the impact of the SNPs on hbeta1AR O-glycosylation, proteolytic processing and cell surface expression using cultured cell lines and isolated neonatal rat cardiomyocytes. We find that the proteolytic cleavage of the receptor is attenuated for the T29 and Q31 variants and enhanced for the G49 variant. The attenuated cleavage of T29 and Q31 variants leads to an increase in the number of full-length receptors at the cell surface. For the Q31 variant, the attenuated cleavage is caused by the disruption of the receptor cleavage site at position R31↓L32, whereas cleavage of the T29 variant is inhibited due to an additional O-glycan found at position 29. In comparison, the existing O-glycan is eliminated at position 49 in the G49 variant. We conclude that the hbeta1AR SNPs affect receptor processing via disrupting the proteolytic cleavage site at R31↓L32 (Q31 variant) or through altered O-glycosylation (T29 and G49 variants). Since the altered glycosylation/cleavage of the beta1AR variants affects the number of functional receptors at the cell surface, it can offer new strategies for drug design and help in understanding the mechanism for the decreased cardiomyocyte beta1AR density in heart failure.
Abstract 14946: Robust Genome Editing of Endothelial Hif-2α in Adult Mice by Ec-Targeted Nanoparticle Delivery of Prime Editing System Inhibits Pulmonary Hypertension
Authors: Peng Yi , Zhao Youyang , Dong Daoyin
Published: June 2023

Introduction:
Prime Editing (PE) is a site-specific mutagenesis approach for highly precise genome editing, thus has the potential for safer editing to treat human diseases. However, the genome editing efficiency has been shown only 5% in adult mice. The in vivo efficacy of prim editing remains unclear.

Hypothesis:
Endothelial cell-targeted nanoparticle delivery of the all-in-one plasmid DNA (15kb) expressing the prime editing under the control of
CDH5
promoter will induce robust genome editing of Hif2a selectively in endothelial cells in adult mice and inhibit PH.

Methods:
To target endothelium for robust genome editing, we employed EndoNP1 nanoparticles to deliver the all-in-one prime editing plasmid DNA under the control of
CDH5
promoter to adult WT and

Egln1
Tie2Cre

mice. The prime editing was designed to change 1-2 nucleotides to introduce a STOP codon in mouse
Hif2a
coding region. Hypoxia-induced PH in mice and

Egln1
Tie2Cre

mouse model of severe PAH were employed to determine the therapeutic potential of prime editing in PH treatment.

Results:
Single administration of mixture of nanoparticles and prime editing plasmid DNA caused 30% genome editing efficacy selectively in endothelial cells of WT mice and also

Egln1
Tie2Cre

mice. The genome editing efficiency was increased to approximately 50% with 2 administrations of the nanoparticle:plasmid DNA mixture in a 1 week interval, resulting in >70% reduction of HIF-2a protein. One week after the 2
nd
administration, WT mice were subjected to hypoxia (10%) for 3 weeks. Pulmonary hypertension was attenuated in the prime edited mice with endothelial Hif2a early stop codon.

Conclusions:
These findings for the first time demonstrate unprecedented efficacy of genome editing of prime editing selectively in ECs of adult mice which exhibit phenotype similar to genetic knockout mice. Thus, EC-targeted nanoparticle delivery of the prime editing system may have great potential for treatment of human diseases associated with endothelial cell dysfunction, such as pulmonary arterial hypertension.
Abstract 14951: An Interpretable Machine Learning Model for Predicting Long-Term Clinical Outcomes in Recurrent Pericarditis
Authors: Yesilyaprak Abdullah , Kumar Ashwin , Furqan Muhammad M , Verma Beni R , Agrawal Ankit , Syed Alveena , Akyuz Kevser , Wang Tom Kai Ming K , Cremer Paul C , Klein Allan L
Published: June 2023

Background:
Recurrent pericarditis (RP) is a complex condition associated with high morbidity. A few studies have evaluated which factors are associated with clinical remission and relapse. However currently, no models exist to predict these outcomes.

Objective:
We developed an explainable machine learning (ML) model that can predict long-term outcomes in patients with RP and enable identification of patients with worse outcomes.

Methods:
Consecutive patients with RP (n=365) from 2012-2019 included. The primary outcome was CR. The dataset was partitioned into training and evaluation sets with 5-fold cross-validation approach. The eXtreme Gradient Boosting (XGBoost) method was used to identify predictors for CR, calculate the likelihood of CR within 5 years, and stratify patients into high-risk and low-risk. The performance of the model was evaluated using the C-index. The log-rank test was utilized to assess the difference between Kaplan-Meier curves of risk groups. Finally, an explainable ML approach, SHAP, was deployed to generate both global and individual explanations of the model’s decisions.

Results:
The cohort was 56% female (n=205) with a mean age of 46 ± 15 years. 61% were idiopathic RP (n=223), 21% were post-cardiac injury syndrome RP (n=77), and 18% were autoimmune RP (n=65) patients. CR was achieved in 32% (n=118). XGBoost risk model included steroid dependency, total no. of recurrences, age, HR, LVEF, gender, etiology, and pericardial delayed gadolinium hyperenhancement as important parameters. The model predicted the outcome with C-index of 0.801 (95%CI, 0.74-0.86) on the validation set and exhibited significant ability in stratification of patients into low- and high-risk groups (log-rank P<0.001).

Conclusions:
We developed a novel ML-based model for predicting CR, and stratifying patients, with high discrimination ability. The use of an explainable ML model can aid physicians in making individualized treatment decision in RP patients.
Abstract 14966: Mechanisms of Protection From Radiation-Induced Endothelial Injury by Statins
Authors: Ait-Aissa Karima , Koval Olha , Lindsey Nathanial , Leng Linette , Grumbach Isabella M
Published: June 2023

Introduction:
The incidental use of statins during radiation therapy has been associated with a decreased risk of long-term atherosclerotic cardiovascular (CV) disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood.

Hypothesis:
Establish the mechanisms by which lipophilic and hydrophilic statins preserve endothelial function after irradiation.

Methods:
Cultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice on day 1 and 10 after head and neck irradiation with 12 Gy were assessed for endothelial dysfunction, nitric oxide and reactive oxidative stress production and various mitochondrial phenotypes.

Results:
Pretreatment of mice with pravastatin or atorvastatin prevented the loss of endothelium-dependent relaxation on day 1 and 10 after head and neck irradiation. Both statins inhibit the loss of nitric oxide, and the increase in cytosolic reactive oxidative stress in endothelial cells. However, only pravastatin blocked mitochondrial superoxide production, mitochondrial DNA damage and loss of electron complex activity. In contrast to atorvastatin, pravastatin also significantly reduced the expression of inflammatory markers TNF-α, NFκB p65 and p50 after irradiation.

Conclusions:
Our findings provide mechanistic underpinnings for the vasoprotective effects of statins after irradiation. While lipo- and hydrophilic statins shield from endothelial dysfunction after irradiation, pravastatin also prevents mitochondrial injury and decreases an inflammatory response by actions in mitochondria. A correlation with clinical studies is necessary to determine whether hydrophilic statins, such as pravastatin reduce the risk of CV disease after irradiation in humans to a greater extent than lipophilic statins.
Abstract 14979: MicroRNA-342-3p Regulates Post-Ischemic Angiogenesis in Diabetic Mice
Authors: Jamaiyar Anurag , Chen Jingshu , Assa Carmel , Cheng Henry , Perez-Cremades Daniel , Feinberg Mark W
Published: June 2023

Introduction:
Diabetic patients are more likely to suffer from adverse cardiovascular events such as myocardial infarction (MI) compared to non-diabetics. Angiogenesis is crucial to limiting infarct size. However, this angiogenic response is blunted in patients with diabetes. MicroRNAs (miRNAs) have been shown to affect both physiological and pathological angiogenesis. However, the role of miRNAs in MI-associated angiogenesis in diabetes remains poorly defined. Here, we describe a novel role of miRNA-342-3p in angiogenesis following ischemic injury to the myocardium.

Methods:
We performed RNA sequencing on cardiac endothelial cells of Ldlr-deficient mice on either chow or high fat sucrose containing (HFSC) diet at 0-, 3-, 7- and 14-days post-MI. Gain and loss of function studies, functional assays, RNA-seq, bioinformatics, RNA-FISH, and light-sheet microscopy were used to ascertain the function and mechanism of this miRNA.

Results:
miR-342-3p was upregulated in cardiac ECs during the vascular remodeling phase post-MI in chow-fed mice compared to the HFSC-fed group. Overexpression of miR-342-3p promotes the number of endothelial sprouts (140% vs control), cumulative sprout length (311% vs control) and scratch closure (AUC 83% vs control, p <0.0001) in endothelial cells (ECs), whereas its inhibition had anti-angiogenic effects. Capillary density and EC proliferation (ki67
+
/CD31
+
) increased by 107% and154% respectively in the border zone of hearts injected with miR-342-3p mimics compared to control in HFSC diet fed Ldlr
-/-
mice 7 days after permanent LAD ligation. Using a combination of RNA-seq and prediction algorithms, Decorin (DCN), a small Leucine rich protein with anti-angiogenic properties, was identified as a target of miR-342-3p. Western blot analysis confirmed significant knockdown of Decorin protein by 94% in HUVECs transfected with miR-342-3p mimics compared to controls. RNA seq profiling of overexpressing ECs implicated the ID1 signaling pathway.

Conclusion:
These results identify a novel role for miR-342-3p in the regulation of angiogenesis post-MI in diabetes. miR-342-3p overexpression rescues impaired angiogenesis in diabetic hearts via the suppression of Decorin, providing new targets for therapeutic angiogenesis.
Abstract 15000: Advanced Hemodynamics in the Assessment of Waitlist Mortality
Authors: Plana Alejandro , Belkin Mark N , Gupta Nikhil , Poonawalla Maria , Siddiki Mikail , Parker William , Pinney Sean , Grinstein Jonathan
Published: June 2023

Introduction:
Our analysis seeks to determine whether it or advanced hemodynamic variables, including aortic pulsatility index (API), pulmonary artery pulsatility index (PAPI), left ventricular stroke work index (LVSWI), or right ventricular stroke work index (RVSWI), correlated more strongly than traditional metrics with waitlist mortality for heart transplant.

Hypothesis:
Advanced hemodynamic markers of cardiac function, including API and PAPI, correlate more strongly with waitlist mortality than traditional hemodynamic criteria, including SBP and PCWP.

Methods:
This retrospective analysis of the Scientific Registry of Transplant Candidates (SRTR) included adults listed at all Statuses after the new heart allocation system in 2018. Hemodynamic data was obtained for patients listed after the 2018 policy change. Kaplan-Meier survival analysis was completed, with API, PAPI, LVSWI, and RVSWI as the independent variable stratified into quintiles.

Results:
There were 9,418 patients listed for heart transplant since the new policy implementation, with 8,636 patients with complete hemodynamic data at listing. Kaplan-Meier survival analysis revealed that API and LVSWI were best at stratifying patients appropriately in terms of waitlist survival with homogeneity of dispersion between groups (Figure 1), (lowest API quintile to highest: HR 2.04, 95%CI 1.94 - 2.15; HR 1.70, 1.59 - 1.81; HR 1.40, 1.29-1.51; HR 1.19, 1.08 - 1.30). The traditional parameters of PCWP, CO and systolic blood pressure had considerable dispersion of risk between quintiles while the right-sided parameters of PAPI and RVSWI did not.

Conclusions:
Advanced left-sided hemodynamic parameters better risk strategy waitlist mortality and the urgent need for heart transplantation than traditional metrics or right-sided advanced parameters.
Abstract 15004: Characterization of Hypertrophic Cardiomyopathy Caused by Mutations in Four and a Half Lim Domains 1 Gene
Authors: Marco Cason , losi Maria-Angela , Borrelli Felice , Calore Chiara , Canciello Grazia , Manganelli Fiore , Tozza Stefano , Bello Luca , Chen Suet Nee , He Lingaonan , Bueno Marinas Maria , Celeghin Rudy , Perazzolo Marra Martina , Todde Gaetano , Frisso Giulia , Taylor Matthew , Pilichou Kalliopi , Lombardi Raffaella
Published: June 2023

Background:
Mutations in Four and Half Lim domain 1 (
FHL1
), an X-chromosome gene, have been described in rare cases of Hypertrophic Cardiomyopathy (HCM), mainly associated with myopathy. The current knowledge of the outcome of HCM caused by
FHL1
mutations relies only on isolated case series.

Objective:
We aim to establish the prevalence of
FHL1
mutations in a large population with overt HCM and clinically characterize HCM patients carrying
FHL1
pathogenic and likely pathogenic genetic variants.

Methods:
From a total population of 794 HCM patients from 3 Referral Centers for hereditary cardiomyopathies, 349 HCM probands, who tested negative for sarcomeric mutations, were genetically screened by using Next Generation Panels including
FHL1
. Moreover, all patients underwent personal and family history collection, physical examination, 12-lead electrocardiogram and echocardiography; while Cardiac Magnetic Resonance (CMR) was performed in a subgroup. Clinical and genetic data of
FHL1
mutation carriers from our cohort were pooled with those of 52
FHL1
positive HCM cases from literature.

Results:
We identified 2
FHL1
pathogenic and 2 likely pathogenic variants (1 missense: c.764G>C; 2 duplications: c.762dup and c.599dupT; and 1 deletion: c.210delG) in 6 HCM probands (0.8% of all HCM and 1.7 % of non sarcomeric HCM). As shown in Fig.1 A, pooled analysis suggested that clinical phenotype of FHL1-HCM was characterized by early-onset, severe diastolic dysfunction independently from the degree of hypertrophy and fibrosis at CMR (Fig 1 B), high sudden death risk, increased incidence of atrial fibrillation and evolution toward heart failure requiring heart transplantation, and variable skeletal muscle involvement.

Conclusions:
HCM patients carrying
FHL1
mutations present with a worse prognosis as compared with the classic sarcomeric-HCM. A better characterization of these patients is needed for a personalized preventive and therapeutic approach.
Abstract 15042: Cardiac-Enhanced Adeno-Associated Viral Vector Achieves Long-Term Transgene Expression in Transplanted Porcine Hearts When Administered During Ex Vivo Perfusion
Authors: Mendiola Pla Michelle , Chiang Yuting , Roki Antonio , Wang Chunbo , Lee Franklin H , Smith Matthew F , Gross Ryan , Evans Amy , Carnes Alexis , Bonadonna Desiree , Glass Carolyn , Bishawi Muath , Schroder Jacob N , Lezberg Paul M , Milano Carmelo A , Bowles Dawn E
Published: June 2023

Introduction:
Use of gene therapy for cardiac transplantation is limited by the lack of an effective recombinant Adeno-associated viral vector (rAAV) gene delivery strategy.
Ex vivo
normothermic perfusion has been increasingly used in clinical practice and is an effective platform for achieving robust global gene delivery to a donor heart. Here we utilized a rationally designed cardiac-enhanced AAV3b variant, SASTG, to deliver the gene firefly luciferase to porcine hearts and evaluated transgene expression 30-days post-transplantation.

Methods:
Heterotopic heart transplantation was performed using blood-type and MHC matched Yucatan pigs (n=4). Donor hearts underwent
ex vivo
perfusion for 2-hours with perfusate containing the rAAV SASTG-Luciferase. Three different doses of rAAV were used: 2x10
13
, 8x10
13
, 1x10
14
viral genome copies (VGC). Recipients were survived for 30 days at which time they were euthanized and donor and recipient hearts were examined for overall levels of luciferase activity, luciferase DNA copy number, and histology for luciferase expression on immunostaining and evidence of inflammation.

Results:
There was a dose-dependent response in luciferase activity observed in the donor heart ventricles with the lowest activity detected at the 2x10
13
VGC dose (1.5-9.9x10
3
RLU/mg) mid-level activity at the 8x10
13
VGC dose (32.7-71.2x10
3
RLU/mg) and highest activity at the 1x10
14
VGC dose (27.6-278.1x10
3
RLU/mg). Luciferase DNA was detectable in a dose-dependent manner in the donor heart ventricles (0.02-131.1x10
3
VGC/pg of DNA), but undetectable in all native hearts. Finally, immunostaining demonstrated diffuse luciferase expression in the donor heart but none in the recipient hearts. There was also no evidence of inflammation in any of the donor hearts.

Conclusions:
The cardiac-enhanced AAV3b variant, SASTG, is associated with robust, global transgene expression in porcine cardiac allografts when administered during
ex vivo
perfusion.
Abstract 15067: Stress Hyperglycemia on Hospital Admission Drives the Risk of Re-Hospitalization for Chest Pain in INOCA Patients
Authors: Mone Pasquale , Wang Xujun , Salemme Luigi , Cioppa Angelo , Popusoi Grigore , Pansini Antonella , Tesorio Tullio , Santulli Gaetano
Published: June 2023

Introduction:
Ischemia with non-obstructive coronary arteries (INOCA) is a relatively new condition, often observed in patients with angina. However, the exact pathophysiology of INOCA is not fully understood, and its management remains very debated.

Hypothesis:
We hypothesized that admission hyperglycemia in INOCA patients could be associated with the risk of being re-hospitalized for chest pain.

Methods:
We evaluated INOCA patients referred to our Institution between 2016 and 2021 for percutaneous coronary intervention (PCI). We divided our population in quintiles according to the values of the stress hyperglycemia ratio (SHR), calculated as the ratio of admission blood glucose (expressed as mmol/L) and HB1Ac (%). We calculated Kaplan-Meier product limits for cumulative ratio of reaching the endpoint and we applied the log-rank test. To further confirm our results, we performed a multivariable analysis in order to adjust for potential confounders.

Results:
2874 INOCA patients were enrolled in our study. At 1-year follow-up, the risk of hospitalization for chest pain was progressively higher in patients with higher SHR values (p<0.001). To rule out the impact of potential confounders, we performed a multivariable analysis adjusting for potential risk factors for re-hospitalization, including age, BMI, hypertension, dyslipidemia, diabetes, smoking, and creatinine; this analysis confirmed the significant association of admission SHR and re-hospitalization in INOCA patients.

Conclusions:
To the best of our knowledge, this is the first report showing that admission SHR is an independent risk factor for hospitalization in INOCA patients, with or without diabetes. Our data indicate that hyperglycemia may trigger coronary microvascular dysfunction driving worse outcomes in this class of patients; in this context, glycemic control may be a main goal to be achieved in this population. Further studies in larger populations and with a longer follow-up are warranted to confirm our findings.
Abstract 15080: Higher Mortality Risk in Very Severe Aortic Stenosis Associated With Atrial Fibrillation
Authors: Ibrahim Hossam H , Thaden Jeremy J , Fabre Katarina L , Scott Christopher G , Pislaru Sorin , Nkomo Vuyisile T
Published: June 2023

Background:
Atrial fibrillation (AF) in severe aortic stenosis (AS) is associated with worse outcomes compared to sinus rhythm (SR). The prevalence of AF and its impact on outcomes in very severe AS (vsAS) is unknown.
Objectives:
To determine the prevalence and prognostic significance of AF in vsAS.

Methods:
A total of 563 patients with vsAS (transaortic valve peak velocity ≥5 m/sec) were identified retrospectively out of 3139 with aortic valve area ≤1.0 cm
2
or ≤0.6 cm
2
/m
2
and left ventricular ejection fraction (LVEF) ≥50%. Patients were divided by rhythm (AF vs SR) at the time of index transthoracic echocardiogram. Outcomes in AF versus SR were compared in propensity-matched analyses (2 SR:1 AF).

Results:
AF was present in 50/563 patients (9%) and SR in 513/563 (91%). In propensity-matched analyses (100 SR:50 AF), the mean age was 83.2±7.3 years, 54% were female. There was no difference in comorbidity index (p=0.84). There was no difference in AF compared to SR in aortic valve area (0.7±0.1 vs 0.7±0.1 cm
2
, p=0.94), peak velocity (5.3±0.3 vs 5.3±0.3 m/sec, p=0.32), LVEF (63±7 vs 65±7%, p=0.14) or E/e’ (23±13 vs 21±12, p=0.48), but patients with AF had larger left atrial volume index (60±16 vs 48±15 mL/m
2
, p<0.001), higher right ventricular systolic pressure (52±15 vs 41±16 mmHg, p<0.001), and higher prevalence of moderate or more tricuspid regurgitation (33% vs 5%, p<0.001) and right ventricular systolic dysfunction (23% vs 6%, p=0.003). Age-, sex-, comorbidity index-adjusted all-cause mortality was higher in AF vs SR (HR 2.33 [1.40, 3.87], p=0.001) (
Figure: Observed overall survival
). Aortic valve replacement (AVR) was associated with improved survival (HR 0.44 [0.25, 0.76], p=0.004) with no evidence of interaction of AVR and rhythm (p=0.15).

Conclusion:
AF was not uncommon among patients with vsAS and identified a subset of patients with vsAS at much higher risk of mortality. Whether AVR should be considered earlier in vsAS when associated with AF needs to be investigated.
Abstract 15087: Chronic Inhibition of NADPH Oxidase Improves Coronary Endothelial Function in Mice With Diabetes
Authors: Wang Lina , Song Yi , Zhang Zhiqi , Feng Jun
Published: June 2023

Introduction::
Endothelial dysfunction is the leading cause for diabetes (DM) related coronary heart disease. Diabetes is associated with NADPH Oxidase (Nox) overproduction and related ROS amplification in endothelial cells and coronary vasculature, which may contribute to coronary endothelial dysfunction. Small conductance calcium-activated-potassium (SK) channels also play a key role in diabetes-induced coronary endothelial dysfunction
. Hypothesis:
Chronic inhibition of Nox may improve coronary endothelial function/coronary arteriolar relaxation, and SK activator-induced vasodilation in mice with or without diabetes.

Methods:
Wild type (control), non-diabetic (ND) mice and genetically modified, obesity/type-2 diabetic mice (BKS.Cg-

Dock7
m

+/+

Lepr
db

/J) with or with treatment with Nox inhibitor apocynin (n = 4-6/group) were used in the study. In the Nox inhibitor treated group, apocynin (30mg/kg/day, i.p) was applied to the diabetic mice for 4 weeks. Small coronary arteries (70-120μM) isolated for harvested hearts were pre-contracted and examined in the presence or absence of the vasodilatory agents, SNP, ADP, and NS309, respectively.

Results:
After 4-week treatment with apocynin, endothelium-NO-dependent relaxation responses to ADP, and endothelium-dependent, SK channel activator NS309 in the diabetic mice were significantly increased when compared with that in untreated diabetic mice, respectively (# p<0.05 vs ND
Figure
). There were no significant differences in responses to the endothelium-independent vasodilator SNP (P>0.05) among the three groups.

Conclusions:
Chronic inhibition of Nox appears to improve coronary endothelial function/coronary relaxation and SK channel activity in mice with diabetes.
Abstract 15091: Cardiac Ct-Guided Exclusion of Left Atrial Appendage Thrombus Prior to Electrical Cardioversion for Atrial Fibrillation
Authors: Cahnbley Melina , Sengupta Jay , Casey Susan A , Witt Dawn R , Cavalcante Joao , Berger Justin , Caye David , Langeberg Tamara
Published: June 2023

Introduction:
Transesophageal echo (TEE) is routinely used to exclude left atrial appendage (LAA) thrombus prior to direct current cardioversion (DCCV) for atrial fibrillation (AF). However, the COVID-19 pandemic accelerated the use of non-invasive modalities such as cardiac computed tomography (CCT) to avoid aerosolizing viral particles during intubation, such as with introduction of a TEE probe. CCT is not routinely used as a clinical strategy to exclude LAA thrombus prior to DCCV. Therefore, we sought to determine the feasibility of CCT-guided DCCV.Hypothesis: CCT-guided elective cardioversion for atrial arrhythmias is a feasible modality to rule out left atrial appendage thrombus.

Methods:
We identified patients at Abbott Northwestern Hospital who underwent CCT in lieu of or in addition to TEE within 24 hours of elective DCCV for AF or atrial flutter from March 2020 to February 2022. Thirty-day outcomes were collected including cerebrovascular accident (CVA), myocardial infarction, cardiovascular death, re-hospitalization, arrhythmia recurrence, and overall mortality. Delayed imaging, 90 seconds after arterial phase, was obtained to exclude LAA thrombus.

Results:
Thirty-two patients were included in our analysis, 10 (31%) were female. Ten (31%) presented with new-onset of AF. CCT did not identify LAA thrombus in any patient. Post-DCCV, the mean time to arrhythmia recurrence was 16.5 days (SD: 9.3). At 30 days, 11 (34%) had been re-hospitalized but mostly for elective procedures. There was no CVA or mortality reported at the 30-day follow-up.

Conclusion:
CCT-guided elective cardioversion for atrial arrhythmias was evaluated for feasibility in a small pilot. In patients who had no LAA thrombus on CCT and subsequently underwent cardioversion, there were no CCT-related complications, CVA, or deaths at 30 days. Many patients benefit from early DCCV rather than waiting with uninterrupted anticoagulation. CCT guidance is a feasible alternative to TEE but needs further prospective comparison to TEE and uninterrupted anticoagulation in this clinical setting.
Abstract 15095: A Rare Cardiomyopathy Caught Offsides: Discovery of a New Phenotype
Authors: Malik Nitin , Hsu Steven , Mazel Jay A , Calkins Hugh G , Judge Daniel P , Barnett Christopher F
Published: June 2023

A 51-year-old male with Wolff-Parkinson-White (WPW) syndrome, atrial flutter, and third-degree heart block necessitating pacemaker placement presented with asymptomatic atrial flutter. The patient’s father and paternal aunt were diagnosed with WPW and died suddenly at approximate ages of 40 and 60 years, respectively. An echocardiogram showed RV dilation and moderate to severe RV systolic dysfunction with normal LV ejection fraction. Cardiac CT demonstrated thinning of the RV free wall and free wall outpouchings during systole (Figure), as well as moderate asymmetric LV hypertrophy, aneurysmal changes of the basal inferior wall, and dyskinesis of the LV apex. At this time, the differential for RV dysfunction included group 1 pulmonary hypertension, ischemic cardiomyopathy, sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy (ARVC). Subsequent testing excluded all diagnoses other than ARVC. Additionally, 2010 Task Force Criteria for ARVC were not met. However, genetic testing revealed p.Arg302Gln mutation in the PRKAG2 gene. AMP-activated protein kinase (AMPK) is a highly conserved kinase encoded by the PRKAG2 gene that is responsible for controlling cellular energy homeostasis. This PRKAG2 mutation, within the spectrum of genetic mutations resulting in the rare autosomal dominant PRKAG2 syndrome, is characterized by glycogen storage cardiomyopathy and a familial form of WPW, supraventricular arrhythmias, and left ventricular hypertrophy. To the best of our knowledge, this is the first report of PRKAG2 syndrome with prominent abnormalities of the RV, and it expands the scope of PRKAG2 syndrome. Management included implantation of an AICD and ongoing careful monitoring for arrhythmia and heart failure. The patient’s siblings and children were referred for genetic counseling. This case highlights the importance of a broad differential diagnosis and exhaustive evaluation of patients presenting with right ventricular abnormalities.
Abstract 15101: Return-to-Work for Patients in High-Risk Professions Diagnosed With a Sudden Death-Predisposing Genetic Heart Disease
Authors: Kulkarni Veda K , Tobert Kathryn E , Bos Johan M , Cowl Clayton T , MacIntyre Ciorsti , Giudicessi John R , Ackerman Michael J
Published: June 2023

Introduction:
Sudden cardiac arrest (SCA) and death (SCD) are the most serious sequelae of many genetic heart diseases (GHDs). Increased awareness of this has led to increased detection in employment screenings. For patients in high-risk jobs, premature and potentially unnecessary termination from their profession, rather than “Return-to-Work (RTW),” has become an undesired consequence of this awareness. The objective of this study is to evaluate the outcomes of patients with GHDs in high-risk professions who were allowed to RTW.

Methods:
We performed a retrospective review of 3,641 working-age patients referred for evaluation of a potential GHD between 6/2000-12/2021 to identify those either in or being recruited into a high-risk profession. A profession was defined as “high-risk” if it is safety-sensitive or required regular medical evaluations. Charts were reviewed for medical history, RTW decision making, and breakthrough cardiac events (BCEs).

Results:
Overall, 33 patients [(0.9%); 3 females (9%); mean age at diagnosis 25 ± 15 years] had been either put on hold from their high-risk job (n = 15; 45%) or disqualified as a recruit (18; 55%) prior to our evaluation due to their GHD diagnosis. This included 15 military, 10 pilots, 6 law enforcement and first responders, and 2 commercial driver license professionals and recruits. Most patients were diagnosed with Long QT syndrome (n = 23; 70%). After treatment initiation, 14 (93%) professionals and 16 (89%) recruits received physician RTW approval while 3 (9%) patients did not receive RTW approval due to disease severity and/or unwillingness to initiate treatment. Of the remaining 14 professionals that received physician RTW approval, 4 (29%) were not allowed to return to their jobs, while 14/16 recruits (88%) were not permitted to start their career. None of the RTW-approved patients had a BCE after evaluation (160.7 follow-up years).

Conclusions:
Patients with GHDs in high-risk professions are often terminated due to perceived SCA/SCD risk. However, within our small cohort, the risk of BCEs in optimally treated patients was low. This data suggests that the certification process of individuals in these high-risk and safety-sensitive occupations should be further examined and potentially modified.
Abstract 15110: Objective Quantification of Disease Severity in Patients With Long Covid
Authors: Verduzco-Gutierrez Monica , Cabrera Juan , Lopez Marielisa , Sathyamoorthy Mohanakrishnan , Shah Sachin A , Loli Akil
Published: June 2023

Introduction:
Patients with Long Covid have been described to present with over 55 subjectively reported symptoms with the most prevalent being fatigue and cardiopulmonary (e.g. chest pain, dyspnea). Objective quantification of the magnitude of disease severity in Long Covid patients using standardized validated tools is needed.

Methods:
This is a retrospective evaluation of patients referred to Flow Therapy for the management of Long Covid symptoms from Jan 2021 to Jan 2022. Patients were included if having complete data for 6 validated tools: PROMIS Fatigue score (range 0-20), Seattle Angina Questionnaire (SAQ) Summary Score (range 0-100), Duke Activity Status Index (DASI, range 0-58.2), 6-minute walk test (6MWT, range 0-unlimited), Rose Dyspnea Scale (RDS, range 0-4) and CCS angina class (CCS, range 1-4). The unpaired student’s t-test or the Fisher’s exact test were utilized for all analyses.

Results:
A total of 100 patients were included for analyses (age 54.2±14.5years, 60% female, 41% with CAD). The baseline PROMIS Fatigue, SAQ, DASI, and 6MWT were 15.8±3.6, 58.6±24.5, 12.9±12.7, and 1199.6±428.3 feet respectively. Moderate to severe dyspnea (RDS) or angina (CCS) was reported in 81% and 61% of patients respectively. When limiting to those without CAD (n=59), the PROMIS Fatigue was 15.7±3.4 compared to 16.0±3.6 in those with CAD (p=0.719). When limiting to those under the age of 41 (n=19), the PROMIS Fatigue was 15.9±4.0 compared to 15.8±3.5 in those 41 years or older (p=0.9466). No correlation was evident between age and PROMIS Fatigue score (r=0.107). SAQ and RDS were not different between the CAD and non-CAD patients (all p-values>0.111). There was no difference across all endpoints when comparing those under 41 versus 41 years or older (all p-values>0.087).

Conclusion:
Our data indicate a moderately high degree of disease severity using 6 validated markers assessing Long Covid symptoms. The validity of scores in patients with Long COVID applies to both patients with concurrent epicardial disease and patients without known epicardial disease. The severity of fatigue in Long Covid patients under 41 is similar to those 41 years or older. Our data provide a paradigm to more objectively diagnose Long Covid.
Abstract 15119: Diastolic Peak Wall Stresses in Marfan vs Non-Marfan Ascending Thoracic Aortic Aneurysm: A Propensity Score Analysis
Authors: Patel Sohil , Zamirpour Siavash , XUAN Yue , Dsouza Sara , Wang Zhongjie , Suarez-Pierre Alejandro , Lawton Jennifer S , Ge Liang , Tseng Elaine E
Published: June 2023

Introduction:
Marfan syndrome (MFS) carries a risk of aortic dissection and death. The current aneurysm repair guideline of diameter ≥5cm may neglect up to 15% of MFS patients who dissect at smaller diameters. Since dissection can occur biomechanically when wall stress exceeds tissue strength, patient-specific biomechanics may enhance risk stratification for MFS patients. The goal of this study was to compare aneurysm wall stresses between propensity score-matched MFS and non-MFS aneurysm patients.

Methods:
The cohort consisted of 5 MFS and 42 non-MFS patients with aortic aneurysm. Preoperative CTA or MR scans were used to create 3D hexahedral meshes. Finite element analysis was performed with MFS and nonMFS material properties to determine peak (99th percentile) diastolic stresses[TE1] . Propensity scores were calculated by logistic regression using age, sex, height, hypertension, diabetes, smoking history, valve type, and sinus diameter. Five pairs were formed by 1:1 optimal matching without replacement. Comparisons used the paired t-test.

Results:
Diameters were similar at the sinus but lower for MFS at the STJ (3.4±0.5 vs 3.9±0.7cm, p=0.003) and the ascending aorta (3.1±0.5 vs 4.3±0.5cm, p<0.001). Peak circumferential stresses (CS) were similar between MFS and nonMFS aneurysms across all regions. As well, peak longitudinal stresses (LS) were similar between the two cohorts across all regions (Fig 1).

Conclusion:
Both CS and LS were similar at all regions for MFS vs non-MFS patients. Because LS has been implicated in acute dissection and LS were similar, differences in tissue strength, rather than wall stress, are most likely causes of high dissection rates in MFS due to material weakness from fibrillin mutation.
Abstract 15165: Dobutamine Stress Echocardiography in Patients With Low Flow, Low Gradient Aortic Stenosis and Preserved Lvef
Authors: Mogensen Nils Sofus Borg S , Carter-Storch Rasmus , Annabi Mohamed-salah , Grenier-Delaney Jasmine , Moller Jacob , Ovrehus Kristian Altern , Pibarot Philippe , Clavel Marie-Annick A , Dahl Jordi Sanchez
Published: June 2023

Introduction:
Guidelines recommend the use of Dobutamine stress echocardiography (DSE) in case of low flow low gradient aortic stenosis (LFLG AS) when left ventricular ejection fraction (LVEF) <50%, but few data support this threshold as most studies have tested DSE when LVEF <35%.

Hypothesis:
To examine the feasibility of DSE in patients with LFLG AS, and the possible interaction between LVEF and accuracy of projected aortic valve area (AVA
proj
) in correctly classifying severe AS defined by Cardiac Computer Tomography (C-CT).

Methods:
Patients with LFLG AS (aortic mean gradient <40 mmHg & AVA <1.0 cm
2
& stroke volume index (SV
i
) <35ml/m
2
) undergoing DSE were identified from two prospective cohorts, and stratified according to LVEF (<35%, 35-50% and >50%). Severe AS was defined as AVC score ≥2000 AU in males, and ≥1200 AU in females on C-CT.

Results:
Of 214 patients, 65 (30%) presented with LVEF <35%, 58 (27%) with LVEF 35-50%, and 91 (43%) with LVEF >50%. 97 patients presented with severe AS (32 vs 21 vs 44, p=0.26). An inverse relationship was seen between LVEF and left ventricular diameter (60±10mm vs 54±7mm vs 47±6mm, p<0.01).

Although resting SV
i
was different between groups (26.4±6.4mL vs 27.3±5.6 vs 29.6±5.7, p<0.01), no significant differences in SV
i
change was seen during DSE (7.3±5.9mL vs 5.5±6.2mL vs 6.7±6.7mL, p=0.30), and patients with LVEF <35% were more likely to demonstrate flow-reserve, defined as an increase in SVi >20%; 39 (63%) vs 21 (36%) vs 44 (49%), p=0.01.

AVA
proj
provided similar AUCs (p=0.31) (Figure 1) and cut-off points in classifying severe AS across LVEF groups: LVEF<35%: 1.02 cm
2
/accuracy 74%, vs LVEF 35-50%: 0.82cm
2
/accuracy 72% vs LVEF >50%: 0.9cm
2
/accuracy 65%.

Conclusion:
DSE leads to similar increases in stroke volume index (SV
i
) in patients with LVEF >50% compared with LVEF ≤50%. Furthermore, the projected aortic valve area (AVA
proj
) provides good accuracy for identification of true-severe AS, regardless of LVEF stratum.
Abstract 15182: Recruiting Super-Relaxed Myosin to Restore Contractility in Human Right Heart Failure
Authors: Jani Vivek , Aslam Imran , Fenwick Axel , Ma Weikang , Gong Henry , Nissen Devin , Cubero Salazar Ilton M , Hanselman Olivia , Abovich Arielle , Mukherjee Monica , Margulies Kenneth B , Cammarato Anthony , Irving Thomas , Kass David A , Hsu Steven
Published: June 2023

Intro:
Right ventricular (RV) dysfunction worsens outcomes in pulmonary hypertension (PH) due to heart failure with reduced ejection fraction (HF), yet underlying mechanisms are unknown. We previously reported RV myofilament max calcium-activated tension (T
max
) is reduced in human PH-HF. Here, we reveal that this decline is due to more myosin heads in the super-relaxed (SRX) state which lack force-production due to low ATP turnover.

Methods:
Frozen RV myocardium from 25 PH-HF and 9 control patients were permeabilized and myocyte mechanics and small angle X-ray diffraction measured.

Results:
RV T
max
(16±4 vs. 23±3 mN/mm
2
, p<1x10
-15
) and peak power (0.06±0.01 vs. 0.11±0.03, p=7.9x10
-5
) were 50% lower in HF. Unsupervised machine learning (infinite mixture Dirichlet process) using mechanics identified two HF subgroups distinguished by RV T
max
: Group 1 with slightly reduced T
max
(19±1 mN/mm
2
, p=3.8x10
-6
) and Group 2 with 40% reduced T
max
(14±3 mN/mm
2
, p<1x10
-15
), with Group 2 exhibiting clinically overt RV failure vs. Group 1 (right atrial pressure, RAP 14±6 vs. 9±4, p=0.01; RAP/pulmonary capillary wedge ratio 0.7±0.3 vs. 0.4±0.2, p=0.047). To test if low RV T
max
was associated with more SRX myosin, X-ray diffraction patterns from RV myofibers were used to determine the equatorial intensity ratio (I
1,1
/I
1,0
), an indicator of myosin proximity to the thick filament backbone. The ratio was lower (more SRX), which was associated with reduced myosin ATP turnover in Group 2 vs. both 1 (p=9.0x10
-7
) and controls (p=1.8x10
-9
). We then tested the effect of SRX on T
max
by perturbing the proportion of SRX myosin using mavacamten (M), a myosin inhibitor that stabilizes the SRX state, and deoxy-ATP (dATP), a nucleotide that destabilizes SRX. In group 2, dATP augmented T
max
by 30% (p=0.0002) while M had no effect (p=0.1); meanwhile in group 1, M suppressed T
max
by 30% (p=0.0002) while dATP had no effect (p=0.9). Finally, a myosin activator EMD-57033, which increases probability of actin-myosin binding, augmented T
max
(correlation between ΔSRX-ΔT
max
r=-0.55, p=0.01).

Conclusion:
We find increased SRX myosin contributes to RV myofilament and chamber-level failure in PH-HF. Small molecules that recruit SRX myosin may have therapeutic benefit in patients with RV dysfunction.
Abstract 15194: Nitrative Modification of Caveolin-3, a Novel Mechanism Revealing Cardiac Insulin Resistance in Ischemic Heart Failure
Authors: Wang Yajing , Meng Zhijun , Zhao Jianli , Yao Peng , Zhang Ling , Zhang Zhen , Xie Dina , LAU Wayne Bond , Christopher Theodore , Lopez Bernard L , Zhu Di , Liu Demin , Gao Erhe , Ischiropoulos Harry , Koch Walter J , Ma Xinliang L
Published: June 2023

Introduction:
Myocardial insulin resistant is a hallmark of diabetic cardiac injury. However, underlying molecular mechanisms remain unclear. Recent studies show that diabetic heart is resistant to other cardioprotective interventions, including adiponectin and pre-conditioning. The “universal” resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad pro-survival signaling cascades. Caveolin (Cav) is a scaffolding protein coordinating transmembrane signaling transduction. However, role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure (HF) is unknown.

Methods and Results:
Mice were fed normal diet (ND) or high-fat-diet (HFD) and subjected to myocardial ischemia and reperfusion. The cardioprotective effect of insulin was significantly blunted as early as 4 weeks of HFD feeding (pre-diabetes), when insulin signals remain unchanged. However, Cav3/IRβ complex formation, requisite for insulin transmembrane signaling, was significantly reduced. Among multiple post-translational modifications altering proteins interaction, Cav3 (not IRβ or AdipoR1) tyrosine nitration is prominent in the pre-diabetic heart. SIN-1 treatment reduced the signalsome formation and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr
73
is the Cav3 nitration site. Phenylalanine substitution of Tyr
73
(Cav3
Y73F
) abolished SIN-1 induced Cav3 nitration, restored Cav3/IRβ complex, and rescued insulin transmembrane signaling. AAV9-mediated cardiac Cav3
Y73F
re-expression blocked HFD-induced Cav3 nitration, preserved Cav3 signalsome integrity, and rescued insulin protective action against ischemic HF. Finally, diabetic nitrative modification of Cav3 at Tyr
73
also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling.

Conclusion:
Nitration of Cav3 at Tyr
73
and resultant signal complex dissociation is responsible for cardiac insulin/adiponectin resistance in the pre-diabetic heart, contributing to ischemic HF progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic HF.
Abstract 15229: An Artificial Intelligence Deep Neural Network Analysis of the 12-lead Electrocardiogram Distinguishes Patients With Congenital Long Qt Syndrome From Patients With Acquired Qt Prolongation
Authors: Bos Johan M , Liu Kan , Attia Zachi , Noseworthy Peter A , Friedman Paul , Ackerman Michael J
Published: June 2023

Introduction:
Over 100 FDA-approved medications, electrolyte perturbations, and many disease states can prolong the QTc beyond its 99
th
percentile value resulting in acquired QT prolongation. In contrast, approximately 1 in 2000 people have congenital long QT syndrome (LQTS) hallmarked by pathological QT prolongation secondary to genetic defects in the heart.

Hypothesis:
An artificial intelligence (AI) deep neural network (DNN) can distinguish patients with LQTS from those with acquired QT prolongation.

Methods:
The study cohort included all patients with LQTS evaluated in the Windland Smith Rice Genetic Heart Rhythm Clinic and controls from Mayo Clinic’s ECG data vault comprising over 2.5 million patients. For the AI-DNN model, every patient/control with ≥ 1 ECG above age- and sex- specific 99
th
percentile values for QTc [> 460 ms for all patients (male/female) < 13 years of age, or > 470 ms for men and > 480 ms for women above this age] was included. An AI-DNN involving a multi-layer
c
onvolutional

n

eural

n

etwork (CNN) was developed to classify patients. LQTS patients were age- and sex- matched to controls at 1:5 ratio.

Results:
Among the 1,599 patients with genetically confirmed LQTS, 808 had ≥ 1 ECG with QTc above the threshold (2,987 ECGs) compared to 361,069/2.5M controls (14% of Mayo Clinic patients getting an ECG, ‘presumed negative’; 989,313 ECGs). Following age- and sex- matching and splitting, 3,309 (training), 411 (validation) and 887 (testing) control ECGs were used. This model distinguished LQTS from those with acquired QT prolongation with an AUC of 0.896 (accuracy 85%, sensitivity 77%, specificity 88%, PPV 0.58, NPV 0.94). After exclusion of patients with a wide QRS (>150 ms) or pacemaker, the model remained successful in distinguishing the two groups (AUC 0.85, accuracy 78%, sensitivity 78%, specificity 87%, PPV 59%, NPV 94%).

Conclusions:
For patients with a QTc exceeding its 99
th
percentile values, this novel AI-DNN functions as a LQTS mutation detector being able to identify patients with abnormal QT prolongation secondary to a LQTS-causative mutation rather than acquired QT prolongation with a >50% positive predictive value. This algorithm may facilitate screening for this potentially lethal, yet highly treatable, genetic heart disease.