bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15036: Suppression-Replacement Gene Therapy for
CALM1
-Mediated Long QT Syndrome
Authors: Tobert Kathryn E , Hamrick Samantha K , Gluscevic Martina , Tester David J , Kim CS John , Ackerman Michael J
Published: June 2023

Introduction:
Calmodulin (CaM)-mediated long QT syndrome (CaM-LQTS) is a genetic arrhythmia disorder characterized by a high prevalence of life-threatening ventricular arrhythmias occurring very early in life, frequent T-wave alternans, markedly prolonged QT intervals (QTc > 600 ms), and intermittent 2:1 AV block. Three distinct genes (
CALM1
,
CALM2
, and
CALM3
) all encode for the identical CaM protein. Conventional LQTS pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with CaM-LQTS. Here, we developed a
CALM1 “
suppression-replacement (SupRep)” gene therapy with the goal of rescuing the prolonged cardiac action potential duration (APD) and increased Ca
2+
amplitude (ΔF/F0) in patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a patient with
CALM1
-mediated LQTS.

Methods:
Custom designed
CALM1
-targeting shRNAs were tested for knockdown efficiency using TSA201 cells and RT-qPCR. A dual-component SupRep
CALM1
gene therapy was created by cloning into a single construct a custom-designed
CALM1
shRNA that produces knockdown (suppression) and a “shRNA-immune” (shIMM)
CALM1
cDNA (replacement). Patient-specific CALM1-F142L iPSC-CMs were generated from a patient with severe LQTS (QTc = 515 ms). FluoVolt voltage-sensing dye was used to measure the APD at 90% repolarization (APD
90
). Calcium transient amplitude was measured using Fluo-4 indicator.

Results:
Overall, 6 unique candidate
CALM1
-targeting shRNAs were tested for knockdown efficiency in a transient transfection
CALM1
over-expression TSA201 cell system. One candidate shRNA had an 80% knockdown efficiency of
CALM1.
Following transfection with
CALM1
-SupRep gene therapy, the APD
90
was significantly decreased in F142L iPSC-CMs compared to untreated cells (F142L: 665 ± 9 ms [n=40] vs F142L + SupRep: 353 ± 9 ms [n=20], p<0.0001). Ca
2+
amplitude was significantly decreased following SupRep transfection when compared to untreated cells (0.99 ± 0.04 vs 0.8 ± 0.06, p=0.02).

Conclusions:
Here, we provide the first proof-of-principle SupRep gene therapy for CALM1-mediated LQTS.
CALM1
-SupRep gene therapy shortened significantly the pathologically prolonged APD
90
in
CALM1
-F142L patient-derived iPSC-CMs.
Abstract 15051: A Large Mitral Valve Vegetation in a Patient Presented With Low Back Pain and Lower Limb Weakness- A Success Story of a Multidisciplinary Team
Authors: Bodruddoza Kazi , Majumder Eshita
Published: June 2023

Case presentation:
A 58-year-old gentleman presented to A&E with low back pain for a few days and lower limb weakness for 24 hours. His background history was not medically significant. On examination, GCS 14/15, lower limbs power 2/5, and palpable urinary bladder. DRE revealed poor anal tone. MRI spine showed epidural abscess at L3-L4 & L5-S1 level and urgent decompressive spinal surgery was performed. IV antibiotics were started and the patient was admitted to the general HDU for vasopressor support. Since the operation, he developed cold, pale, swollen right leg, with no palpable peripheral arteries. A CT aortogram showed occlusion of the right popliteal artery. Right popliteal artery exploration with anterior and posterior tibial embolectomy and fasciotomies were done. As the patient was slow to wake up post-surgery, he was transferred to ICU. MRI brain showed no pathology. Transthoracic echocardiogram revealed no vegetation. As clinical suspicion of infective endocarditis was high, transoesophageal echocardiogram and real-time 3D analysis was done which showed a large highly mobile echogenic mass attached to the left atrial surface of the anterior mitral leaflet (A1 and A2) causing moderate MR. Urgent surgical mitral valve repair and removal of a 2 cm vegetation were performed. Both the blood culture and the culture of the vegetation tissue confirmed the growth of Staphylococcus aureus (MSSA). After 8 weeks of hospital stay, the patient was discharged home.

Discussion:
The objective of this case presentation is to reemphasize that infective endocarditis is not a single organ disease and can present to different specialities. Transthoracic echocardiography has reduced sensitivity in the critical care setting. So, there should be a relatively low threshold for transoesophageal echocardiography. Although the mortality rate of infective endocarditis is relatively high in ICU patients, multidisciplinary team management may result in favourable outcomes.
Abstract 15052: A Young Patient Who Presented With Dilated Cardiomyopathy and Renal Infarction During Treatment With Isotretinoin
Authors: Napoli Gianluigi , De Feo Daniele , Carella Maria Cristina , Forleo Cinzia , Favale Stefano , Pepe Martino
Published: June 2023

Background:
Isotretinoin or 13-cis-retinoic acid (RA) is one of the most effective and widely used drug for the treatment of severe acne vulgaris. Despite deemed safe, no definite consensus has been reached on the cardiovascular risk of RA derivatives. We describe the first case of concomitant dilated cardiomyopathy (DCM) and renal infarction after 5 months of isotretinoin use in a previously healthy 18-years old man.

Case Summary:
An18-years-old man, with history of acne vulgaris, presented in August 2021 to our emergency department because of left iliac fossa pain and effort dyspnea. Computed tomography scan revealed left renal infarction and echocardiogram demonstrated global left ventricular (LV) dilatation with severely reduced LV-ejection fraction (LVEF: 29%). Coronary artery disease, autoimmune, infective, or heritable causes of DCM were ruled out. Cardiac magnetic resonance evidenced LV circumferential mid-wall late gadolinium enhancement and ECG monitoring revealed several non-sustained ventricular tachycardia episodes. Thus, Bisoprolol, Sacubitril/Valsartan, and Eplerenone were started and up titrated until maximum tolerated doses, with only poor LVEF improvement.

Conclusion:
Our case aims to raise awareness on rare life-threatening cardiovascular events associated with isotretinoin use for the treatment of severe acne in young patients. To the best of our knowledge, this is the first described case of renal thromboembolism and DCM requiring S-ICD implantation and cardiac transplant program listing occurring in the course of isotretinoin treatment.
Abstract 15058: Critical Reappraisal of Genetic Variants in Hypertrophic Cardiomyopathy
Authors: Alzate Aguirre Mateo , Pumarejo Andredi , Zanjirani Farahani Nasibeh , Giudicessi John , Arruda-Olson Adelaide A , Bos Johan M , Ackerman Michael J
Published: June 2023

Introduction:
Hypertrophic cardiomyopathy (HCM) is a disease characterized by genotypic and phenotypic heterogeneity. Correct classification of genetic variation is critical for clinical interpretation. Herein, variants of uncertain significance (VUS) pose a dilemma in clinical practice, limiting physicians’ decision making and causing anguish to patients and family members. Furthermore, with increasing knowledge and changing guidelines, continuous reassessment is crucial to maintain usefulness in practice. This study sought to assess contemporary variant classification in a large cohort of patients with HCM.

Methods:
Retrospective analysis of all patients with HCM seen at Mayo Clinic and all patients with a variant in one of 8 genes with strong disease association for HCM were included. Genetic test reports were obtained from electronic health records along with their original variant classification assigned by either a commercial or research laboratory. Reassessment of variant pathogenicity was performed using the 2015 ACMG guideline criteria. Population frequency was obtained using Gnomad. Co-segregation presence or absence was determined by family history and co-segregation studies. Combined Annotation Dependent Depletion (CADD) was used as computational evidence of genetic deleterious effects for single nucleotide variants.

Results:
Between 2003 to 2019, a total of 1,782 patients underwent laboratory or commercial HCM genetic testing. Of these, 787 (44%) had positive genetic test with a variant at least 1 of the 8 genes. The original pathogenic classification was obtained for 754 patients. Of those, 430 (57%) variants where within the gene MYBPC3, 244 (32%) within MYH7 and 80 (11%) within either ACTC1, MYL2, MYL3, TINNI3, TNNT2 or TPM1. Overall, 222 patients (29%) originally had one or more variants classified as a VUS. Upon reassessment, 120 (54%) were reclassified as either pathogenic (33%), likely pathogenic (58%), benign (5%) or likely benign (3%).

Conclusion:
Periodic reassessment for HCM genetic variants, especially VUS, is critical for adequate patient care and management. Cascade screening could decrease patients’ uncertainty regarding their prognosis and management.
Abstract 15061: Role of Exosomal Microrna-21a-5p in the Modulation of Ischemia-Induced Angiogenesis in Hypercholesterolemic Conditions
Authors: Raguema Nozha , Dussault Sylvie , Luo Yi Hui , Desjarlais Michel , Rivard Alain
Published: June 2023

Introduction:
Extracellular vesicles (EVs) and their MicroRNA (miR) content are involved in several physiological processes, including the response to ischemia and angiogenesis. Hypercholesterolemia (HC) is an important cardiovascular risk factor associated with impaired angiogenesis and ischemia-induced neovascularization. However, the effect of HC on the modulation of miR content in EVs in the setting of tissue ischemia is unknown.

Hypothesis:
We tested the hypothesis that HC causes alterations in the miR content of EVs related to ischemia/neovascularization, and that engineered EVs can be harnessed as angiogenic vectors to promote angiogenesis and therapeutic neovascularization in this situation.

Methods:
We used a mouse model of peripheral artery disease to induce severe ischemia in the hindlimbs of hypercholesterolemic ApoE
-/-
and control C57Bl/6J mice. Microvesicles (MVs) and exosomes (exo) were isolated from ischemic skeletal muscles by differential centrifugation. Total RNA was extracted from these 2 types of EVs, and the miR content was analyzed using next generation sequencing. Selected miRs were transfected in EVs and the angiogenic capacity of the engineered EVs was assessed in vitro using a Matrigel assay.

Results::
Bioinformatic analysis of the 100 most expressed miRs in EVs showed an enrichment of several miRs in EVs compared to ischemic skeletal muscles. Interestingly the highly expressed miR-21a-5p, which has previously been shown to have angiogenic properties, is specifically enriched in exo. Moreover, we found that miR-21a-5p expression is reduced in exo isolated from ischemic skeletal muscles in hypercholesterolemic conditions. We next forced miR-21a-5p expression in exo, and found that these engineered exo significantly increase tube formation in HUVECs.

Conclusions:
We show that several angiogenic miRs are enriched in EVs in the setting of tissue ischemia, and that HC can alter EV miR profile in this situation. miR-21a-5p, which expression is reduced by HC, was identified as an important modulator of exo angiogenic activity. Exo engineered to overexpress miR-21a-5p could eventually constitute a novel therapeutic strategy to promote neovascularization and reduce ischemic damages in severe vascular diseases.
Abstract 15063: Liver Gene Regulatory Mechanisms of Variants at Lipid and Cardio Metabolic Trait Loci
Authors: Pandey Gautam , Currin Kevin , Vadlamudi Swarooparani , Moxley Shelley , Nicholas Jayna , McAfee Jessica , Broadaway Alaine , Mohlke Karen
Published: June 2023

Genome-wide association studies (GWAS) have identified hundreds of risk loci for cardiometabolic and lipid-related traits. GWAS loci are enriched in tissue-specific transcriptional regulatory elements that affect target gene expression driving physiological changes. Most GWAS variants are located in non-coding regions, which makes identifying functional variants and target genes challenging. Previously, we identified GWAS signals colocalized with molecular quantitative trait loci for liver gene expression (eQTL) and liver accessible chromatin (caQTL) to predict regulatory variants for lipid and cardiometabolic traits. These caQTLs are rs13395911, rs11644920, rs34003091 and rs9556404 associated with liver enzymes, LDL-cholesterol, and triglycerides. To evaluate the predicted mechanisms, we tested these variants with surrounding regulatory elements for allelic effects on transcriptional reporter activity and for effects on target gene expression in HepG2 cell line. Along with the two previously reported intronic caQTL variants, rs13395911 and rs11644920
,
we observed significant (P<0.05) allelic differences in transcriptional activity for rs9556404 and rs34003091, located at the promoters of
GPR180
and
ZNF329
, respectively. Based on eQTL and HiC data, the predicted genes for intronic enhancers rs13395911 and rs11644920 are
EFHD1
and
LITAF
, respectively. To confirm the target genes for these two variants, we deployed inducible CRISPRi system by stably expressing dCas9 fused to a KRAB-repressor domain in HepG2 and targeting guide RNAs (gRNAs) to the DNA elements that span caQTL variants. For each element, we introduced ≥6 gRNAs into cells via lentiviruses and measured gene expression using qPCR. Compared to pools of non-targeted control gRNAs, preliminary analyses using pools of enhancer-targeting gRNAs surrounding rs13395911 and rs11644920 led to 30.3% lower
EFHD1
and 38.6% lower
LITAF
expression at 7 days post-transduction, respectively. Thus, we identified and validated mechanisms by which DNA variants alter transcriptional activity and identified the target genes for lipid-related GWAS loci. These results suggest that this framework can be scaled up to map thousands of enhancers to genes in their native genomic state.
Abstract 15076: Decisional Regret in Patients Undergoing Transcatheter Aortic Valve Replacement Procedure
Authors: kanwar Amrit , Jolly George , Ali Saif , Kashner Michael T , Silvet Helme
Published: June 2023

Introduction:
Decisional regret has been associated with reduced quality of life and lower satisfaction with care and is an important patient-reported outcome, which has not been studied in patients undergoing TAVR (transcatheter aortic valve replacement) procedure. In our study, we used a simple Decision Regret Scale to evaluate decisional regret in veterans and their family members after TAVR.

Methods:
Demographic, clinical characteristics, death outcomes and results of Decision Regret scale administered to patients and/or family member were recorded for all subsequent subjects referred for TAVR by a single VA medical center between October 2013 and September 2020. Data were analyzed using Cox regressions.

Results:
Study included 124 patients (Table 1) who were followed from the TAVR date until censored date or death for a mean of 939 days (range 3-2,487 days). During this time, 67 patients (54%) died, with comorbidities predicting death (Charlson’s comorbidity index by Cox multivariable regression, p=0.002). Using a mean regret scale with 0 being no regret and 100 being overwhelming regret, patients had a mean regret scale of 7.95 ± 11, whereas family had a mean regret scale of 20.36 ± 31 (most family responders were in patients who had already died). By exploratory analysis, decisional regret was not associated with higher likelihood of predicted death (patient responders, p= 0.6; family responders p=0.2). Patients were more likely to report that decision for the procedure was a joint decision with the physician (55% patient vs 36% family responders), whereas family was more likely to report that patient alone had made the decision.

Conclusions:
After initial adoption, TAVR procedure in veteran patients was associated with high mortality, primarily due to existing comorbidities. Surviving patients themselves had a low level of decisional regret regarding TAVR compared to moderate regret expressed by family members, mostly reported after patients had died.
Abstract 15116: Left Ventricular Adaptation to Aortic Regurgitation in Adults With Repaired Coarctation of Aorta
Authors: Goda Ahmed , ABOZIED OMAR , Andi Kartik , Ramachandran Dhanya , Egbe Alexander C
Published: June 2023

Background:
Aortic regurgitation (AR) can develop in adults with repaired coarctation of aorta (COA), but there are limited data about left ventricular (LV) remodeling and clinical outcomes in this population. The purpose of the study was to compare LV remodeling (LV mass index [LVMI], LV ejection fraction [LVEF], and septal E/e’) and onset of symptoms before aortic valve replacement (AVR), and LV reverse remodeling (%-change in LVMI, LVEF and E/e’) after AVR in patients with versus without repaired COA presenting with AR.

Methods::
Asymptomatic adults with repaired COA presenting with moderate/severe AR (AR-COA group) were matched 1:2 to asymptomatic adults without COA and similar severity of AR (control group).

Results:
Although both groups (AR-COA n=52, and control n=104) had similar age, sex, body mass index, aortic valve gradient, and AR severity, the AR-COA group had higher LVMI (124±28 versus 102±25 g/m2, p<0.001) and E/e’ (12.3±2.3 versus 9.5±2.1, p=0.02) but similar LVEF (63±9% versus 67±10%, p=0.4). COA diagnosis (adjusted HR 1.95, 95%CI 1.49-2.37, p<0.001), older age, E/e’, and LV hypertrophy wereassociated with onset of symptoms. Of 89 patients (AR-COA n=41, and control n=48) with echocardiographic data at 1-year post-AVR, the AR-COA group had less regression of LVMI (-8% [95%CI -5 to -11] versus -17% [95%CI -15 to -21], p<0.001) and E/e’ (-5% [95% CI -3 to -7] versus -16% [95% CI -13 to -19], p<0.001).

Conclusions:
Patients with COA and AR had a more aggressive clinical course, and perhaps may require a different threshold for surgical intervention.
Abstract 15125: L-Arginine and Vitamin C Improve Symptoms of Long-COVID: Results of a Nationwide Multicenter Study
Authors: Izzo Raffaele , Trimarco Valentina , Mone Pasquale , Aloe Teresita , Capra Marzani Massimo , Diana Antonello , Fazio Giovanni , Mallardo Mario , Maniscalco Mauro , marazzi giuseppe , Messina Nunzia , MININNI SIMONE , Mussi Chiara , Pelaia Girolamo , Pennisi Alfio , Santus Pierachille , Scarpelli Francesco , Tursi Francesco , Zanforlin Alessandro , Trimarco Bruno , Santulli Gaetano
Published: June 2023

Introduction:
Mounting evidence indicates that endothelial dysfunction and oxidative stress play crucial roles in the pathophysiology of COVID-19 and Long-COVID.

Hypothesis:
We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects on Long-COVID symptoms.

Methods:
We designed a nationwide multicenter clinical study, in which a survey assessing several symptoms that have been previously associated with Long-COVID was administered to COVID-19 survivors; the subjective perception of the tolerance to the effort was measured as well, trough the Borg scale. Patients were divided in two groups, with a 2:1 ratio: the first group included patients treated with L-Arginine + Vitamin C, whereas the second group was treated with multivitaminic combinations (alternative treatment). Before administering the survey, patients completed 30 days of treatment.

Results:
1590 patients were initially enrolled, of which 1390 successfully completed the study. Following a 30-day treatment with L-Arginine + Vitamin C, the survey revealed that patients in this treatment group had significantly lower scores compared to the other group. There were no other significant differences between the two groups. Furthermore, when examining the subjective perception of the tolerance to the effort (modified Borg scale), we observed a significantly lower value (p<0.0001) in the L-Arginine + Vitamin C patients compared to the alternative-treatment arm.

Conclusions:
Our findings indicate for the first time that the supplementation with L-Arginine + Vitamin C has favorable effects in Long-COVID, in terms of reducing its typical symptoms and improving the perceived tolerance to effort.
Abstract 15126: Hybrid Supervised and Unsupervised Machine Learning Model Improves Prediction of New-Onset Dialysis in Orthotopic Heart Transplant Patients
Authors: Mathi Roshan , McDonald Weston , Usry Benjamin , Shorbaji Khaled , Welch Brett , Kilic Arman
Published: June 2023

Introduction:
Machine learning (ML) approaches to clinical risk prediction have demonstrated improved performance over traditional statistical approaches. New-onset dialysis following isolated orthotopic heart transplantation (OHT) is an important contributor to mortality risk and quality of life in recipients, yet traditional approaches to predicting its occurrence have performed only modestly. This study sought to develop and evaluate a hybrid supervised and unsupervised ML approach to estimating the risk of new-onset dialysis following OHT.

Methods:
This was a retrospective study of patients (n = 26,505) with no history of dialysis undergoing primary, isolated OHT between 2000 and 2022 as identified in the United Network for Organ Sharing (UNOS) database. The study cohort was split randomly into training (80%) and validation sets (20%) and under-sampling using K-Nearest Neighbors clustering was used to account for class imbalance. ML models, including a Multilayer Perceptron Classifier, a Support Vector Classifier, and a Logistic Regression Model were developed and compared. Sensitivity, accuracy, precision, and F
1
score were measured, and discriminatory performance was assessed using the area under the receiver-operating-characteristic curve (AUC).

Results:
The rate of new dialysis was 11.3% following OHT with comparable rates in the training and validation cohorts. In the validation cohort, the support vector classifier had the highest AUC Score (0.774 (95% CI, 0.748 - 0.800), sensitivity (0.74), F
1
Score (0.72), accuracy (0.70), and precision (0.70). All other models yielded poorer performance by every metric. Predictive risk factors that were common across models included congenital heart disease, pre-transplant glomerular filtration rate, and human leukocyte antigen mismatch.

Conclusions:
This study demonstrates that an ML approach using a support vector model was associated with improved model performance metrics including discriminatory capability compared to other modeling approaches in predicting new-onset dialysis risk after OHT. The use of ML models in OHT may have utility in patient selection, modification of risk factors, and programmatic evaluation.
Abstract 15135: Preliminary Results of a Randomized Controlled Feasibility Study of an Intervention to Facilitate End-of-Life Discussions in Implantable Cardioverter Defibrillator Recipient and Informal Caregiver Dyads
Authors: Miller Jennifer , Chung Misook L , Durante Angela , Latimer Abigail , Hodges Dustin , Hesselson Aaron , Czarapata Mary M , Peppiatt Cecil , Moser Debra K
Published: June 2023

Introduction:
Mean survival following implantable cardioverter defibrillator (ICD) implantation is 2.5 years with 13% of ICD recipient deaths related to arrhythmic mechanisms and 37% related to end-stage heart failure. Despite the relatively short survival expectancy and potential of death from other causes most ICD recipients do not participate in advance care planning discussions. Information regarding communication of EOL choices between ICD recipients and informal caregivers is sparse.

Objective:
To determine feasibility of an internet-based dyadic communication intervention to facilitate EOL conversations between ICD recipients and informal caregivers using the Hello game, a question-based card game.

Methods:
The feasibility of this intervention was determined by ease of recruitment, study drop out, and participant evaluation of the intervention using a Likert-style questionnaire (0-5 with 5 being the highest rating) and open-ended questions to gather additional information to enhance the quality of the intervention.

Results:
From January 2021 to July 2022, a total of 38 ICD recipient (70% male, 91% white, 60 years
+
11) and informal caregiver (29% male, 100% white, 56 years
+
12) dyads of 97 approached (39%) in the outpatient electrophysiology clinic of an academic medical center participated in this randomized control pilot study. The majority of those who declined participation cited not having enough time. Eleven dyads (29%) dropped out after completing the consent process. No significant baseline differences were noted between the control and intervention groups. One hundred percent of intervention completers (N=9 dyads) expressed comfort regarding the intervention and highly rated the content 4.11
+
.86, presentation and presenter 4.10
+
.82, technology use 4.17
+
.60, comfort 3.46
+
.61, and conversation 4.11
+
.90.

Conclusion:
Preliminary results indicate that this intervention is feasible and acceptable to ICD recipients and informal caregivers.
Abstract 15136: Matrix Mechanics Regulate Engineered Myocardial Microtissue Organization and Contractility
Authors: DePalma Samuel J , Stis Austin E , Huang Darcy , Jilberto Javiera J , Lo Jason , Davidson Christopher D , Chowdhury Aamilah , Jewett Maggie E , Helms Adam S , Nodsletten David A , Baker Brendon M
Published: June 2023

Introduction:
The mechanical function of the myocardium is dictated by cardiomyocytes (CMs) and the surrounding fibrous extracellular matrix (ECM). Due to limitations in existing approaches for engineering myocardial tissue, how CMs sense and respond to mechanical microenvironmental changes remains understudied. Here, we established a method for creating arrays of cardiac microtissues with highly tunable mechanical features by integrating synthetic, fibrous matrices and iPSC-CMs. Through real-time contractility readouts enabled, we explored how biomechanical cues influence engineered cardiac tissue assembly and function.

Methods:
Arrayed cardiac microtissues were generated by selectively photo-crosslinking electrospun dextran vinyl sulfone fiber matrices onto pairs of microfabricated PDMS cantilevers. Subsequently, iPSC-CMs were patterned onto matrices using a microfabricated seeding mask. Matrix and cantilever stiffnesses were tuned by adjusting photoinitiator concentrations and cantilever geometry, respectively.

Results:
In tissues contracting against soft cantilevers (0.41 N/m), tissue contractile stress decreased with increasing matrix stiffness (E = 0.68 to 17.3 kPa). We also observed an increase in contractile stress on soft and aligned matrices, compared to non-aligned matrices. However, tissues contracting against stiffer cantilevers (1.2 N/m) exerted similar contractile stresses independent of matrix alignment. This may be explained by the enhanced alignment of myofibrils in non-aligned matrices contracting against stiffer posts. The size of vinculin-rich cell-ECM adhesion decreased on stiff matrices. Vinculin also localized to z-discs forming organized costameres on soft matrices. Tissue response to mavacamten suggests that β-cardiac myosins are required for costamere formation and myofibril maturation.

Conclusions:
We developed a new microfabrication strategy to create tunable cardiac microtissues and examined how biomechanical cues affect tissue assembly and function. We found that matrix stiffness, matrix alignment, and tissue constraint distinctly affect iPSC-CM function and structure, potentially due to differential influences on costamere formation and myofibrillar assembly.
Abstract 15138: Lower Extremity Arterial Calcification: Association With Walking Impairment in Patients With Peripheral Arterial Disease
Authors: Rimmerman Eleanor T , Patel Surina A , Chou Ting-Heng , Janse Sarah A , Bobbey Adam J , Atway Said A , Go Michael R , Stacy Mitchel R
Published: June 2023

Introduction:
Increasing prevalence of arterial calcium in the lower extremities of patients with peripheral arterial disease (PAD) is associated with worsening clinical outcomes. Calcium burden can be detected in patients using standard imaging methods. However, quantitative evaluation of calcium burden in specific arteries of the leg in PAD patients is uncommon in the clinical setting, and the association between quantified levels of vessel-specific calcium burden and functional capacity in PAD remains understudied. We hypothesized that x-ray computed tomography (CT) imaging could quantify calcium mass of the superficial femoral (SFA) and popliteal artery and CT-derived measures of calcium burden would be associated with walking impairment scores.

Methods:
Healthy controls (n=8) and patients with PAD (n=44) underwent CT imaging of the legs. Calcium mass was quantified from CT images by manual segmentation of the combined SFA and popliteal artery from axial images, with established calcium defined as arterial segments with CT image intensities >130 Hounsfield units. To assess functional capacity, the Walking Impairment Questionnaire (WIQ) was administered at the time of imaging. Univariate and multivariate analyses were performed to assess the association between calcium measures and walking impairment scores.

Results:
WIQ scores for distance, speed, and stairs significantly differed between healthy controls and PAD patients (all scores, p<0.0001). Calcium mass values for the SFA-popliteal artery were significantly higher in PAD patients versus healthy controls (p=0.0005). In univariate analysis, WIQ scores for distance (p=0.004), speed (p<0.001), and stairs (p=0.002) were significantly associated with calcium mass of the SFA-popliteal artery. Associations between WIQ scores and SFA-popliteal artery calcium mass remained significant after adjusting for age and body mass index in multivariate analyses.

Conclusions:
These results suggest that calcium burden above the knee is significantly associated with walking impairment. Implementation of arterial calcium scoring for the lower extremities in PAD patients may provide novel insight into the relationships between calcium burden, PAD symptoms, and functional limitations.
Abstract 15145: Aldehyde Dehydrogenase 2 Agonist Reverses Fibroblast Activation in the End Stage Human Right Ventricle Failure via 3’Utr Regulation of Profibrotic Genes
Authors: Neupane Rahul , Cieslik Katarzyna A , Youker Keith , Palaniyandi Suresh S , Ashrith Guha , Thandavarayan Rajarajan A
Published: June 2023

Background:
Cardiac fibrosis, a prominent feature of pressure overloaded right ventricle (RV) in pulmonary hypertension (PH), is fundamental to the development of right ventricle failure (RVF). We found that a defect in alternative polyadenylation (APA) of profibrotic genes is a driving factor that induces fibrosis. Oxidative stress-mediated reactive aldehydes, such as 4-hydroxy-2-nonenal (4HNE) contribute to fibrosis and extracellular matrix (ECM) remodeling. However, the role of 4HNE in APA is unknown.

Methods:
We compared isolated cardiac fibroblasts from the RVs of explanted transplanted hearts of recipients with pulmonary hypertension patients to control hearts.

Results:
Compared to controls, tissue and fibroblasts derived from failing RV human hearts have greater deposition of extracellular matrix (ECM) proteins, such as collagen type I alpha (COL1A) and fibronectin (FN1), the expression of alpha smooth muscle actin (α-SMA), indicative of myofibroblast differentiation, and nuclear factor kappa B subunit (NFκB), a transcription factor critical for profibrotic genes transcriptional activation. Moreover, alternative polyadenylation (APA) isoforms of mRNA for COL1A, FN1, NFκB, TGF-β1 and its receptor - transforming growth factor beta receptor 1 (TGFβR1) are associated with shortened 3’UTR in RVF tissues or fibroblasts. Likewise, reduced expression and activity of aldehyde dehydrogenase 2 (ALDH2) expression, a 4HNE detoxifying enzyme, correlated with increased 4HNE adduction in tissues and cardiac fibroblasts derived from RVF hearts. Moreover, ALDH2 activation by its agonist, Alda-1, decreased 4HNE adduction and oxidative stress and most importantly downregulated the gene and protein expression of profibrotic genes, simultaneously lengthening the 3’UTR of the previously shortened profibrotic genes.

Conclusion:
In RVF, fibroblasts express mRNA of profibrotic genes with shortened 3'UTRs, suggesting the feasibility of developing antifibrotic therapies targeting 3'UTRs in myofibroblasts. Furthermore, our findings suggest that Alda-1 has a therapeutic role in mitigating cardiac fibrosis in RVF hearts by attenuating 4HNE-mediated dysregulation of APA.
Abstract 15152: Contributing Causes of Death in US Males With Muscular Dystrophy Across the Lifespan
Authors: Giafaglione Jaclyn , Nandi Deipanjan , Hayes Emily , Wright Lydia
Published: June 2023

Introduction:
The muscular dystrophies are a group of disorders affecting skeletal, cardiac, and respiratory muscles. Advances in care have been reported to have shifted mortality from respiratory to cardiac etiology in cohort studies. Changes in cause of mortality at the population level using Untied States national death certificate data were assessed.

Methods:
The
CDC Wonder
database was queried for male muscular dystrophy patients in the US utilizing the ICD 10 code G71.0. Cause of death and age were evaluated between 1999 and 2020 in 1 year increments. Distribution of death age was compared between those who died with heart failure and those who died with respiratory failure as contributing causes of death. Trends in median death age over time were evaluated for all groups.

Results:
There were a total of 12,109 deaths attributed to muscular dystrophy over the study period. Heart failure contributed to 2,419 (20%) of deaths, while respiratory failure contributed to 3,763 (31%). Deaths overall were most common in the 3
rd
decade of life, while those who died with contributory heart failure died earlier compared to those with contributory respiratory failure (Figure A). The median death age has increased over time for all causes (p= <0.001), though the magnitude of the change was smallest and median death age remained lowest for those with heart failure as a contributing cause (Figure B).

Conclusions:
While death certificate data may be incomplete and not represent the full muscular dystrophy cohort, this data supports that the median death age for patients with muscular dystrophy is increasing over time. Those with heart failure contributing to death continue to die at younger ages, suggesting opportunities for further improvement in cardiac care for these patients.
Abstract 15154: Association of Social Isolation/Lack of Social Network With Stroke: A Systematic Review and Meta-Analysis of Prospective Studies
Authors: Desai Rupak , Mondal Avilash , ODUGBEMI OLUFEMI , Kodali lakshmi Spurthi , Gara Sirisha K , Devakumar Sahana , Jitta Sahas Reddy , Yalla Naga Amrutha Sai , Juveria Fnu , Li Aobo , Bambhroliya Zarna , Vyas Ankit
Published: June 2023

Background:
Social isolation (SI) or loneliness affects overall morbidity, but its influence as a cerebrovascular risk factor is understudied. This review aims to assess the long-term impact of social isolation on stroke risk.

Methods:
PUBMED, Scopus, and EMBASE were systematically searched for prospective studies reporting stroke/cerebrovascular outcomes of lack of social contact/network or SI. A stroke/systemic embolic event was the primary endpoint. Pooled relative risk and heterogeneity were assessed with random-effects models and I
2
statistics, respectively. Subgroup analysis was performed based on follow-up duration and mean/median age of patients. Leave one out sensitivity analysis was performed. A funnel plot was used for visual assessment of publication bias. A p<0.05 was considered a threshold for statistical significance.

Results:
A total of 9 prospective studies were included between 2006 and 2021(N=177,591, mean age: 53- 67 years) reporting patients with a lack of social support/network or, SI. 5 studies from the US and rest from other high-income countries. A total of 5657(3.3%) stroke events were recorded in a median follow-up duration of 10.25 years. Pooled analysis revealed a higher odds of stroke in SI vs non-SI cohorts on adjusted (OR 1.37 95%CI 1.13-1.65, p= 0.01) analysis
[Fig. 1]
. Subgroup analysis indicated a higher risk of stroke in studies with a follow-up duration of <10 years vs >10 years (1.47 vs 1.20, p=0.01)
[Fig. 2]
and in studies with more elderly participants [mean/median ≥60 years vs <60 years (1.45 vs 1.22, p<0.001)]
[Fig. 3]
.

Conclusions:
Our findings suggest that lack of social contact/network or social isolation is associated with an increased risk of developing stroke over a median follow-up of a decade, especially in older individuals. Future studies are needed to investigate whether interventions targeting social isolation can help to prevent one of the leading causes of death and disability in high-income countries.
Abstract 15162: Anomalous Right Coronary Artery From the Left Sinus of Valsalva With an Interarterial Course: Impact on Clinical Outcomes in the Adult Population
Authors: Warner Eric , Gulati Aishwarya , Halpern Ethan , Fischman David L , Ruggiero Nicholas J , Keith Scott W , McCarey Melissa , Savage Michael P
Published: June 2023

Introduction:
Anomalous right coronary arteries (RCA) arising from the left sinus of Valsalva with an interarterial course (lAC) may cause sudden cardiac death in children and adolescents. However, the natural history and management of patients in whom this anomaly is first detected during adulthood remains uncertain.

Methods:
Database review identified patients ≥35 years old with anomalous coronary arteries diagnosed by cardiac catheterization or coronary computed tomographic angiography. The outcomes of patients with anomalous RCA with IAC treated conservatively were compared to patients with anomalous left circumflex (LCX) coronary arteries with retroaortic course (an anomaly not associated with ischemic events). The primary outcome was all-cause mortality. Secondary outcomes included survived cardiac arrest and myocardial infarction.

Results:
The study population consisted of 185 patients (115 men, 70 women) aged 59 ± 12. Clinical characteristics were similar in the RCA (n=88) and LCX (n=97) groups. At follow-up of 6.6 ± 4.4 years there were no statistically significant differences between the 2 groups in mortality (p=0.11) or in secondary outcomes (P=0.89).

Conclusions:
The outcome of adult patients who had an anomalous RCA with lAC were similar to patients who had anomalous LCX with a known benign course. These results suggest that most patients who survive this anomaly into adulthood may be managed conservatively without intervention.
Abstract 15169: Prediction of Right Ventricular Failure After Left Ventricular Assist Device Implantation: Role of Vasodilator Challenge
Authors: Cacioli Giulio , Polizzi Vincenzo , Ciabatti Michele , Cristiano Ernesto , Pergolini Amedeo , Distefano Giada , Lilla Della Monica Paola , Comisso Marina , Piazza Vito , Sbaraglia Fabio , Musumeci Francesco
Published: June 2023

Introduction:
pulmonary artery pulsatility index (PAPi) is an indicator of right ventricular (RV) function and an independent predictor of right ventricular failure (RVF) following LVAD implantation.

Hypothesis:
Administration of vasodilator challenge during right heart catheterization (RHC) could reduce RV workload allowing a better assessment of its functional reserve.

Methods:
patients undergoing LVAD implantation at our Institution between May 2013 and August 2021 were enrolled. Only patients with RHC and vasodilator challenge with sodium nitroprusside were analyzed. We collected all available clinical, instrumental and haemodynamic parameters, at baseline and after nitroprusside infusion, and we evaluated potential association with post-LVAD RVF.

Results:
of the 54 patients analyzed, 19 (35%) developed RVF after LVAD implantation. RV FAC (OR 0.647, CI 0.481-0.871; p=0,004), PASP (OR 0.856, CI 0.761-0.964; p=0.010) and post-NTP PAPi (OR 0.218, CI 0.073-0.653; p=0.006) were independent predictors of post-LVAD RVF. The model combining RV FAC, PASP and post-NTP PAPi presented a predictive accuracy of 90.7%. Addition of post-NTP PAPi led to increased EUROMACS-RHF risk score (79.4% vs 70.4%; AUC 0.841 vs 0.724, p=0.022) and CRITT score (79.6% vs 74%; AUC 0.861 vs 0.767, p=0.033) predictive accuracy.

Conclusions:
post-NTP PAPi has proven to be an independent predictor of RVF following LVAD implantation. Dynamic assessment of PAPi through vasodilator challenge could represent a test of RV functional reserve in candidates for LVAD implantation. Larger and prospective studies are needed in order to confirm this hypothesis.
Abstract 15172: Improving Cardiac Segmentation for Atrial Fibrillation Ablation: A Prospective Trial of Machine Learned Geometric Dissection vs Experts
Authors: Feng Ruibin , Deb Brototo , Ganesan Prasanth , Tjong Fleur V , Ruiperez-Campillo Samuel , Clopton Paul L , Rogers Albert J , Somani Sulaiman , Rodrigo Miguel , Zou James , Zaharia Matei , Narayan Sanjiv M
Published: June 2023

Introduction:
Segmenting cardiac computed tomography (CT) to provide anatomic guidance for Atrial Fibrillation (AF) ablation is routinely applied, but is time-consuming and prone to error. Machine learning (ML) is a powerful approach that could automate this approach, but is hindered by the small size of available labeled datasets.

Hypothesis:
We hypothesized that a new computational pipeline, in which an ML model is trained mathematically in a small cohort (N=20) using geometrical heart avatars derived from computer graphics imaging (CGI), rather than on manually-segmented data, would enable rapid expert-level segmentation of raw cardiac CT scans.

Methods:
We first encoded anatomical knowledge with generic geometrical avatars and derived a “virtual dissection” method to geometrically parse the heart (Fig A). An ML model trained by virtual dissection using 20 cases was able to rapidly and accurately segment the pulmonary veins (PVs), left atrial appendage (LAA), and left atrium (LA) from cardiac CT scans (Fig B), which we tested in a retrospective study of N=100 patients (30% women, 64.7±10.1Y) and in a prospective clinical trial of N=42 patients (42.9% women, 65.2±10.8Y) undergoing AF ablation, against a panel of 3 experts (Fig C).

Results:
In a retrospective study (N=100), ML achieved median Dice scores of 96.6% (IQR: 95.1% to 97.5%), similar to experts (p<0.05). In a prospective study (N=42), this pipeline reduced segmentation time (2.3±0.8 vs 15.0±6.9 minutes; p < 0.00001; Fig D), but achieved similar Dice scores (93.9% (IQR: 93.0% to 94.6%) vs 94.4% (IQR: 92.8% to 95.7%); p<0.05; Fig E).

Conclusions:
In our prospective trial, virtual dissection (machine learning of cardiac structures based on mathematical cardiac geometry) accelerated cardiac segmentation prior to AF ablation. In general, this approach may reduce the dependence on large training datasets for machine learning, and could be applied to other organ systems for diverse therapeutic strategies.
Abstract 15184: Connective Tissue Disease Subtype and Pregnancy: Risk of Lifelong Thoracic Aortic Aneurysmal Disease
Authors: Nasir Afsheen , Zafar Mohammad , Kalyanasundaram Asanish , Sonsino Alexandra , Papanikolaou Dimitra , Tanweer Maryam , Li Yupeng , Ziganshin Bulat A , elder robert , campbell katherine H , Cohen Lawrence S , Elefteriades John A , Chou Josephine
Published: June 2023

Introduction:
Pregnancy may increase the risk of thoracic aortic aneurysm (TAA) and its complications in connective tissue disease (CTD) patients, but risk by CTD subtype is unclear.

Methods:
Using the Yale Aortic Institute database, we identified 244 female patients with Marfan’s, Ehlers Danlos, or Loeys Dietz Syndromes. We included imaging, clinical, surgical and pregnancy information using retrospective chart review.

Results:
Among MFS patients, 50% were ever-pregnant and had TAA; 20% were ever-pregnant and did NOT have TAA, while 25% were never-pregnant and had TAA. Ever-pregnant MFS had higher rates of Ao dissection (13% vs 7%), Ao surgery (45% vs 20%), and mortality both all cause (11% vs 0) and CV/Ao (5% vs 0).Among EDS patients, only 7% were ever-pregnant and had TAA; 66% were ever-pregnant and did NOT have TAA, while 1% were never-pregnant and had TAA. Overall low rates of Ao dissection (2%), Ao surgery (>1%), and mortality (2% all cause and 0.6% Ao/CV) were seen in ever-pregnant group.LDS population was small. TAA rate and need for Ao surgery were more common in the ever-pregnant group. No dissections or deaths in either group.

Conclusion:
Ever-pregnant patients with MFS had the highest risk of TAA, Ao dissection, Ao surgery and mortality. In contrast, ever-pregnant EDS patients had low rates of TAA and complications. Ever-pregnant LDS may be more likely to develop TAA and need for Ao surgery.
Abstract 15213: Physical Activity Engagement Among African Americans, African Immigrants, Afro-Caribbeans, and Non-Hispanic White Participants in the 2010-2018 National Health Interview Survey (NHIS)
Authors: Ajibewa Tiwaloluwa , Turkson-Ocran Ruth-Alma , Commodore-Mensah Yvonne
Published: June 2023

Introduction:
Physical inactivity rates are increasing, with higher rates among non-Hispanic Black adults compared to their non-Hispanic White counterparts. However, a comparison of physical activity (PA) engagement across Black Ethnic subgroups in the U.S. has yet to be documented. The purpose of this study was to examine PA engagement rates among African American, African immigrant, and Afro-Caribbean adults compared with White adults.

Hypothesis:
We hypothesized that significant differences in adherence to PA recommendations across ethnic groups, with lower adherence to recommendations among the Black Ethnic subgroups compared with their White counterparts.

Methods:
We included data from non-Hispanic White, African American, Afro-Caribbean, and African immigrant adults from the 2010-2018 National Health Interview Survey in these analyses. Using generalized linear models, we compared levels of PA [meeting the moderate-to-vigorous physical activity (MVPA) recommendations] by race/ethnic group adjusting for age and sex.

Results:
Data from 202,273 adults (mean age 48 years; 31% college/graduate degree; 52% female; 32% with obesity) were included. Among the total sample 49.6% of participants met the MVPA recommendations, while 50.4% did not. Unadjusted pooled analysis across the 9-year period, showed that a majority of White participants (52%) adhered to the MVPA guidelines, compared to only 42% of African Americans, 41% of Afro-Caribbeans, and 47% of African immigrants (all
p
s<0.01). Similarly, in adjusted models, higher levels of PA were seen among White adults (52% adhering to MVPA guidelines), compared with African American (41%), Afro-Caribbean (41%), and African immigrant adults (42%) (
p
s<0.01) (Table).

Conclusions:
Higher levels of inactivity are seen across Black subgroups in the U.S. compared with their White peers, likely contributing to higher disease burden, highlighting the importance of focused interventions within these groups.