bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11835: Different Dynamic Luminal Compression of Intramural Segment During Cardiac Cycle in Anomalous Aortic Origin of Coronary Arteries Revealed by Ivus Gated Sequences
Authors: Formato Giovanni Maria , Agnifili Mauro L , Arzuffi Luca , Rosato Antonio , Ceserani Valentina , Zuniga Olaya Karina Geraldina , Secchi Francesco , Deamici Miriam , Conti Michele , Bedogni Francesco , Frigiola Alessandro , Lo Rito Mauro
Published: June 2023

Introduction:
Anomalous Aortic Origin of Coronary Artery (AAOCA) with intramural (IM) segment is associated with risk of sudden cardiac death (SCD). The pathogenic mechanism is believed to be the IM compression caused by the aorta expansion during effort. However, the IM compression occurrence and magnitude during the cardiac cycle remain unknown.

Hypothesis:
We hypothesized that the IM segment is subjected to dynamic compression during different phases of cardiac cycle with a luminal area and roundness smaller in systole than in end-diastole.

Methods:
Lumen dynamics was derived from IVUS pullbacks of N=35 AAOCA (N=23 with IM tract) after retrospective image-based gating to identify cardiac cycles. The cyclic change of area (A) and roundness (R=minimum/maximum lumen axis) of ostial, distal IM, and extramural (EM) tracts were described after manual lumen segmentation. The systolic phase was identified, in each patient, by estimating normal PQ and QT intervals from image-based gating. Results are presented with median and interquartile range. One-tailed Wilcoxon signed-rank test (p<0.025) assessed differences between systolic and diastolic phases in each tract.

Results:
A systolic reduction of roundness was observed in ostium [R
systole
= 0.5 (0.2), R
diastole
= 0.6 (0.3), flattening: -7% (10), p=0.01] and distal IM segment [R
systole
= 0.7 (0.2), R
diastole
= 0.8 (0.2), flattening: -6% (16), p=0.004]. No-IM segments showed normal behaviour and remained circular during the entire cardiac cycle. The distal IM had an area reduction during systole [A
systole
= 8.3 (2.3) mm
2
, A
diastole
= 8.1 (2.9) mm
2
, narrowing: -4% (11), p=0.009] that was not observed in all other segments (Figure 1).

Conclusion:
AAOCA with IM segment has pathological dynamic compression mainly in systole. Studying AAOCA behaviour with IVUS during the cardiac cycle may help to evaluate and quantify the severity of the narrowing.
Abstract 11849: The Influence of Atrial Fibrillation on Mortality Among Cancer Patients
Authors: Fujisaki Tomohiro , Sueta Daisuke , Yamamoto Eiichiro , Tsujita Kenichi
Published: June 2023

Background:
Although atrial fibrillation (AF) is associated with an increased risk of mortality in the general population, it is less studied in cancer patients.

Methods:
Using an observational registry in Japan, adult patients diagnosed with cancer at the Kumamoto University Hospital between 2007 and 2018 were identified. The trend in the prevalence of AF and their effects on all-cause mortality were investigated.

Results:
As many as 30,706 cancer patients were identified, and 19,496 patients were included after excluding patients with significant missing values. The overall median follow-up time was 4.5 years. The prevalence of AF was steady during the study period (n=250, 1.3%), and anticoagulation drugs were used in approximately 90% of patients with CHADS
2
scores ≥ 1. The Kaplan-Meier analysis revealed that AF patients had a lower survival estimate compared with non-AF patients (adjusted HR, 1.23; 95% CI, 1.01-1.49) (Figure 1). Subgroup analyses indicated that AF patients treated with warfarin or without any anticoagulation drugs were associated with poor prognosis (adjusted HR, 1.30; 95% CI, 1.05-1.61, adjusted HR, 1.91; 95% CI, 1.06-3.46, respectively), however, AF patients treated with direct oral anticoagulants were not associated with it (adjusted HR, 0.65; 95% CI, 0.36-1.17) compared with non-AF patients.

Conclusions:
Approximately 1.3% of cancer patients had AF, and the majority received anticoagulation treatments. AF seemed to be associated with poor prognosis among cancer patients, and the extent of association varied across anticoagulation strategies. Further studies are warranted to investigate the influence of AF and its anticoagulation strategies on cancer patients.
Abstract 11854: Intensive vs Standard Blood-Pressure Control ni Individuals With Polyvascular Disease
Authors: Shi Hanyuan , Martinez-Camblor Pablo , Creager Mark A , Henkin Stanislav
Published: June 2023

Introduction:
In the SPRINT trial, intensive blood pressure control reduced all-cause mortality and major adverse cardiovascular events in individuals at high risk for cardiovascular events. However, it is unclear whether individuals with polyvascular disease, compared to individuals without established atherosclerosis, similarly benefit from intensive blood pressure control.

Methods:
We performed a post-hoc analysis of the SPRINT trial to determine the efficacy of intensive versus standard blood pressure control on the primary composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death); and secondary outcomes (cardiovascular death, myocardial infarction). Individuals were stratified by severity of atherosclerosis: no known atherosclerotic disease (Framingham Risk Score > 15%), subclinical atherosclerosis, symptomatic single-bed atherosclerosis, and symptomatic polyvascular atherosclerosis. Uni- and multivariable Cox regression models were used to compute the crude and adjusted hazard ratios. Interaction between intensive vs standard blood pressure control and atherosclerotic burden was evaluated.

Results:
In the SPRINT trial, 6,837 individuals had elevated Framingham Risk Score, 128 had subclinical atherosclerosis, 1,207 had symptomatic single-bed atherosclerosis, and 254 had symptomatic polyvascular disease. There was graded increase in risk of primary composite outcome and secondary outcomes with more atherosclerotic burden, even when controlling for differences in baseline characteristics (Figure). There was no interaction among groups between treatment assignment and primary or secondary outcomes.

Conclusions:
This post-hoc analysis of SPRINT trial demonstrates a higher risk of adverse in patients with escalating atherosclerotic burden. Individuals derive benefit from intensive blood pressure control regardless of burden of atherosclerosis.
Abstract 11869: Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the Multi-Ethnic Study of Atherosclerosis
Authors: Shabani Mahsima , Wang Min , Jenkins Gregory D , Rotter Jerome I , Rich Stephen S , Batzler Anthony , Taylor Kent D , Mychaleckyj Josyf C , Liu Duan , Ac Lima Joao A , Pereira Naveen L
Published: June 2023

Introduction:
Genome-wide association studies have identified common genetic variants associated with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and left ventricular (LV) characteristics. However, the association of these variants with myocardial fibrosis (MF), an important pathophysiological mediator of cardiomyopathy, is unknown.

Hypothesis:
We used the Multi-Ethnic Study of Atherosclerosis (MESA), to evaluate the association of these loci with interstitial MF measured by cardiac MRI (CMR).

Methods:
Unrelated MESA participants with T1-mapping CMR and no history of MI or heart failure were included (n=1,235). We used the extracellular volume (ECV) fraction as a well-established surrogate of interstitial MF. Genotyping was performed by Affymetrix Human SNP array 6.0, and imputation was performed using the TOPMED reference panel. Log ECV(%) was regressed on 50 candidate SNPs, in each ethnicity/race group, adjusting for age, sex, and population stratification principal component. The race-specific results were pooled by fixed-effect meta-analyses using METASOFT.

Results:
The
SMARCB1
rs2186370 intronic variant, previously identified as a risk variant for DCM and HCM, was associated with ECV (p=0.0004). The rs2186370 A allele (frequency: 0.18 in Whites, and 0.50 in African Americans) was associated with a 1.6% increase in ECV. The rs2070458 A allele (another
SMARCB1
intronic variant), in complete linkage disequilibrium with rs2186370, was known previously to be associated with increased LV wall thickness, mass, and concentricity. The direction of effect was similar in all four ancestry groups, but the effect was strongest in African Americans. These variants are strong expression quantitative loci (eQTLs) in human LV tissue and are associated with genotype-dependent expression of
SMARCB1
(
p
=7.3х10
-22
) and
MMP11
(
p
=2.5х10
-24
).

Conclusions:
In conclusion, variants in two linked
SMARCB1
loci previously associated with HCM, DCM and LV traits, are associated with CMR-based interstitial MF. These loci are eQTL not only for SMARCB1 but also for MMP11 an important mediator of MF
.
These findings underscore the important link between MF and CM, and potentially provide novel mechanistic targets in understanding the development of CM.
Abstract 11914: VSIG4+ Resident Tissue Macrophages Govern Cardiac Remodeling and Function After Acute Myocardial Infarction in Mice
Authors: Alayrac Paul , Achab Ali Alexandra , Sun Yanyi , Duval Vincent , Lemitre Mathilde , Vilar Jose , Levoye Angelique , Camus Stephane , Cochain Clement , Silvestre Jean-Sebastien
Published: June 2023

Introduction.
Resident tissue macrophages (RTM) are essential cellular hubs regulating tissue homeostasis beyond their classical immune surveillance functions. Of note, after acute myocardial infarction (AMI), cardiac RTM have been shown to inhibit fibrosis, promote angiogenesis, and foster the anti-inflammatory response to injury by interacting with other immune cell types, such as monocytes and T lymphocytes, to drive them towards pro-healing phenotypes.

Hypothesis.
Using Single Cell RNA Sequencing, we identified a new subpopulation of cardiac RTM characterized by the expression of VSIG4 (B7 family-related protein V-set and Ig domain-containing 4). In this work, we hypothesized that VSIG4+ RTM display protective function in the infarcted heart.

Method and results.
Visg4
deficient mice showed adverse cardiac remodeling and worsened cardiac function at day 14 and 28 after the onset of ischemia when compared to their wild-type littermates. Echocardiography-based transthoracic injection of FACS-sorted cardiac VISG4+ macrophages into infarcted hearts 2 weeks post-AMI, improved cardiac function in both WT and
Vsig4
-/- mice, underlying the protective role of VSIG4+ RTM in this pathological setting. Conversely, injection of
Vsig4
-/- macrophages impaired cardiac function in WT and
Vsig4
-/- animals. VSIG4 deficiency is associated with a higher number of neutrophils, inflammatory monocytes and macrophages but also with a reduction in the amount of CCR5+ regulatory T lymphocytes in the cardiac tissue without any changes in blood, bone marrow and spleen. In cultured peritoneal macrophages, a prototypical example of RTM, IL4 and IL13 stimulation improved VSIG4 mRNA and protein levels through IL4 receptor alpha and IL13 receptor alpha1 activation. IL4 and IL13 treatment also increased secretion of CCL3 and CCL4, two chemokine ligands of CCR5, these effects were blunted in VSIG4 deficient macrophages.

Conclusion.
VSIG4+ RTM are key regulators of cardiac remodeling after AMI likely through their ability to hamper inflammation and recruit protective regulatory T cells in infarcted heart.
Abstract 11916: Differences in Serum Transthyretin Levels Between Wild Type and Hereditary Transthyretin Cardiomyopathy Patients
Authors: Steinberg Rebecca S , Yalamanchili Sreeram , Rim Austin , Rangaswamy Nandakumar Dhanish Revanth , Patel Rahul , Brown Matthew T , Bhatt Kunal
Published: June 2023

Introduction:
Transthyretin (TTR), formerly called prealbumin, is a liver-secreted protein responsible for carrying thyroxine in the serum. Destabilization of TTR tetramers and subsequent deposition in the heart can cause cardiac amyloidosis, either spontaneously in a wild type (ATTRwt) form or in a hereditary form (hATTR). Lower serum levels may serve as prognostic indicators for patients with amyloid cardiomyopathy (CM-ATTR), but these levels can increase over time with the use of stabilization therapies such as Tafamidis.

Hypothesis:
The purpose of this study was to examine how TTR levels differ between ATTRwt and hATTR patients and patient characteristics associated with lower levels of TTR.

Methods:
We conducted a retrospective chart review of patients diagnosed with ATTR-CM with wild type or pV142I mutations enrolled in Emory University's Cardiac Amyloidosis Clinic between January 2014 and February 2022. We compared TTR levels between ATTRwt and hATTR patients at diagnosis, at 1-year follow up, and at 2-year follow up where data was available. We then stratified our cohort by Tafamidis use to compare TTR levels with and without the use of Tafamidis. Data are presented as median [interquartile range] and Mann-Whitney U test was used to compare TTR levels among groups.

Results:
Among 83 patients (22% ATTRwt, 78% hATTR), we found that hATTR patients had lower serum TTR levels at diagnosis compared to ATTRwt patients (wtATTR: 19.2 [14.8, 23.8]; hATTR: 14.3 [9.75, 17.9]; p=0.021), but that 1-year and 2-year TTR levels did not differ between groups. When stratifying by Tafamidis use, we found that there were no significant differences in TTR level at diagnosis and within 1 or 2 years of diagnosis between wtATTR and hATTR patients (Table).

Conclusion:
Patients with hATTR have lower serum TTR levels at diagnosis compared to ATTRwt patients at diagnosis. After Tafamidis use, both wtATTR and hATTR patients have similar levels of TTR.
Abstract 11934: Natural Language Processing Models Can Be Trained to Accurately Recognize the Presence of Disease Within Clinical Notes
Authors: Vidmar David , Thompson Will , Chen Ruijun , Hartzel Dustin , Rocha Daniel , Leader Joseph , Fornwalt Brandon , Haggerty Christopher M
Published: June 2023

Introduction:
Automated methods to “label” the presence of disease such as atrial fibrillation (AF) within electronic health record (EHR) data are important for secondary uses such as population health management. Labels generated from billing code patterns (e.g. “at least 2 relevant ICD codes used within 1 year”) can be accurate within one health system, but may fail to generalize across systems due to variations in coding practices.

Hypothesis:
We hypothesized that a natural language processing (NLP) model could be trained to detect the presence of atrial fibrillation using unstructured clinical notes by learning at scale from labels generated from a validated structured EHR and billing code definition. If successful, this could facilitate scaling disease label methods across large amounts of clinical data without suffering from inaccuracies due to variations in coding practices.

Methods:
We collected clinical notes from a regional health system into a training set of roughly 29 million code-labeled episodes and a separate hold-out set of roughly 1.8 million code-labeled episodes. We trained our NLP model on the training set and computed model performance compared to the code-based labels on the hold-out set. We also performed targeted blinded chart reviews. This work was conducted under IRB approval.

Results:
The model achieved an AUPRC of 0.91 with 87% recall and 89% precision and learned to distinguish challenging confounders despite not being explicitly trained for these tasks (Fig). Blinded review of select episodes showed that the NLP model was correct 90% of the time when it labeled the episode as positive for atrial fibrillation despite the code-based label (incorrectly) labeling it negative.

Conclusions:
NLP models can learn to automatically label the presence or absence of atrial fibrillation within clinical notes and may lead to greater accuracy and generalizability relative to code-based labeling methods.
Abstract 11937: Genetic Cardiomyopathies Misdiagnosed as Isolated Cardiac Sarcoidosis: High-Yield Results of a Systematic Screening Strategy
Authors: Lal Mallika , Chen Christopher , Masha Luke , Camacho Samuel , Masri Ahmad , Nazer Babak
Published: June 2023

Introduction:
Isolated cardiac sarcoidosis (ICS) poses a diagnostic challenge due to its patchy myocardial involvement and low yield of endomyocardial biopsy (EMB). The diagnosis is often suggested by (18)F-fluorodeoxyglucose (FDG) avidity on positron emission tomograpy (PET) scan. Genetic cardiomyopathies (some of which may be FDG-avid) often present with similar clinical manifestations as ICS, so we evaluated a systematic screening strategy in which all patients with suspected ICS were offered genetic testing.

Methods:
We reviewed all patients in our Multi-Disciplinary Sarcoid Consortium for those given a diagnosis of ICS by the referring provider based on FDG-PET scans with myocardial but no systemic FDG avidity. These patients were offered genetic testing with commercially available genetic cardiomyopathy and arrhythmia panels (168 genes).

Results:
Of 110 patients referred, 16 met inclusion criteria, 1 had EMB-proven ICS, 1 did not consent, and 14 were referred for genetic testing. Ten patients (71%) also underwent cardiac MRI, of which 9 had late gadolinium enhancement. Mean age was 61.7±11.6 years, 12 (86%) were male. Mean ejection fraction at time of presentation was 43±10%. Four patients (29%) had presented with atrio-ventricular block, 12 (86%) with ventricular arrhythmias and 12 (86%) with left ventricular systolic dysfunction. Eight (57%) had EMB without granulomas (6 had not undergone EMB). Of these 14 patients, 5 (36%) had pathogenic mutations: 2 in
LMNA,
2 in
TPM1,
and 1 in
MYBPC3
. All 5 patients’ clinical phenotype was consistent with their genotype and 3 had previously been immunosuppressed without clinical improvement or resolution of FDG avidity.

Conclusions:
Genetic cardiomyopathy is often misdiagnosed as “isolated cardiac sarcoid.” A screening strategy of genetic testing all patients with isolated myocardial FDG avidity on FDG-PET scans had a 36% yield for pathogenic mutations and should be considered as part of routine clinical care.
Abstract 11941: Accuracy of OCT Core Labs in Determining Coronary Artery Plaque Composition
Authors: Gruslova Aleksandra , Singh Shashank , Hoyt Taylor , Vela Deborah , Vengrenyuk Yuliya , Buja Louis M , Litovsky Silvio , Michalek Joel , Maehara Akiko , Kini Annapoorna , Akasaka Takashi , Garcia-Garcia Hector , Jang Ik-kyung , Dijkstra Jouke , Raber Lorenz , Milner Thomas , Feldman Marc D
Published: June 2023

Introduction:
Intravascular optical coherence tomography (OCT) provides a high-resolution representation of coronary atherosclerosis. However, the accuracy of OCT image interpretation is unknown. We present a blinded study of histologically identified OCT human plaque composition by leading international OCT core labs.

Hypothesis:
Human readers are unable to accurately identify all plaque compositions.

Methods:
Seven recognized OCT core labs (Japan, Netherlands, Switzerland, USA) participated. Each laboratory was provided 51 OCT image clips recorded from ex vivo human coronary arteries within 24 hours of death and had regions of interest processed for H&E stain. Nine plaque components were identified and are listed in Results. Each OCT core lab was asked to blindly read OCT images and complete a questionnaire indicating one of nine possible plaque types. Kappa coefficient (
k
) was used (
k
< 0.5 poor agreement,
k
> 0.5 high agreement) to measure intra-reader agreement; the median
k
is reported for each plaque component.

Results:
High agreement was demonstrated in identifying stable plaque including fibrous (0.93), calcium (0.83), layered plaque (1.0), and ThCFA (0.63), in contrast to unstable plaque including calcified nodule (0.50), lipid pool (0.35), macrophages/foam cells (0.35), TCFA (0.39), and necrotic core (0.22). When categories were restricted to Fibrous, Calcium, and Lipids, with Lipids expanded to include lipid pool, TCFA, and necrotic core, similar to an OCT core lab definition,
k
for Lipids increased to 0.61.

Conclusions:
Results suggest that participating OCT core labs can accurately identify combined lipid categories (lipid pool, TCFA, and necrotic core), fibrous tissue and calcium. However, accuracy is reduced when reading more sophisticated unstable plaque components. Study results emphasize the need for the development of OCT plaque composition analysis with artificial intelligence.
Abstract 11954: Metabolomic Profiles Differentiate Arterial and Venous Polygenic Risk
Authors: Gilliland Thomas C , Lee Jiwoo , Ruan Yunfeng , Truong Buu , Haidermota Sara , Lannery Kim , Wong Megan , Koyama Satoshi , Natarajan Pradeep
Published: June 2023

Introduction
: Genome-wide association studies reveal genetic correlations between venous and arterial cardiovascular phenotypes, such as venous thromboembolism (VTE), coronary artery disease (CAD), and peripheral arterial disease (PAD). The extent to which these diseases share metabolomic signatures has not been established.

Methods
: Polygenic risk scores (PRS) for CAD, PAD, and VTE were constructed using PRS-CS with external summary statistics and tested on ~120,000 UK Biobank participants with metabolomic profiling. Linear regression adjusted for age, sex, genotyping array, the first five principal components of ancestry, and statin prescription estimated the effect of polygenic disease risk on 249 metabolites among participants free of prevalent cardiovascular disease. For all metabolomic associations common to at least two diseases, bidirectional two-sample Mendelian randomization tested the causal relationship between metabolite and phenotype.

Results
: We found 206, 201, and 116 metabolites were associated with genetic risk for CAD, PAD, and VTE, respectively, at an adjusted p-value of 0.001 (
Figure
). Metabolomic profiles were similar between CAD and PAD (R = 0.75, P = 1.25E-46) and CAD and VTE (R = 0.76, P = 8.27E-49), but not between VTE and PAD (R = 0.24, P = 1.21E-4). Mendelian randomization revealed 28 metabolites that increased risk for both CAD and PAD and 2 metabolites that increased risk for CAD but decreased risk for VTE. There were no metabolites with shared causal relationship between PAD and VTE.

Conclusions
: Polygenic risks for arterial and venous disease are associated with unique metabolomic profiles. Mendelian randomization reveals overlap in causal metabolites between CAD and PAD but little overlap between VTE and either CAD or PAD despite moderate genetic correlation.
Abstract 11958: Incidence of Acute Thrombotic Occlusion and Its Predictors After Contemporary Femoropopliteal Endovascular Therapy in Patients With Peripheral Artery Disease
Authors: NAKAO SHO , Iida Osamu , Asai Mitsutoshi , masuda masaharu , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Tsujimura Takuya , Matsuda Yasuhiro , Hata Yosuke , Uematsu Hiroyuki , Toyoshima Taku , Higashino Naoko , Mano Toshiaki
Published: June 2023

Introduction:
Although there is robust evidence for the superiority of contemporary femoropopliteal (FP)-specific devices to traditional therapy using non-coated balloon or bare metal stent, cohesive reports on the incidence of acute thrombotic occlusion (ATO) after endovascular therapy (EVT) with contemporary FP devices are scarce. This study investigated the incidence of ATO and its predictors after contemporary FP-EVT for peripheral artery disease.

Methods:
We retrospectively examined 763 limbs (chronic limb-threatening ischemia [CLTI]: 44%, involving popliteal arterial lesion: 44%) in 644 patients (mean age: 75±9 years, male: 71%, hemodialysis: 34%) who successfully underwent EVT with contemporary FP devices (drug-coated balloon [DCB]: n=235, scaffold: n=528 [drug-coated stent: n=220, stent graft: n=158, drug-eluting stent: n=150]) from June 2012 to July 2020. The outcome measure was ATO defined as acute onset of claudication and/or signs of CLTI in combination with angiographic evidence of occlusive thrombus formation within the treated segment. Cox proportional hazards regression models were used to identify baseline characteristics associated with the incidence of ATO after contemporary FP-EVT.

Results:
The 24-month incidence of ATO in the overall population was 4.3±0.8% (DCB: 1.0±0.7% versus scaffold: 5.8±1.1%, P<.01). Due to the remarkably lower incidence of ATO after EVT with DCB, risk factors for ATO in patients treated with scaffold was identified. Hemodialysis (hazard ratio [HR]: 2.63, P=.02) and involving popliteal lesion (HR: 8.22, P<.01) were independently associated with an increased risk of ATO. The 24-month incidence of ATO in patients with those risk factors was 21.0±3.3%, while that in patients without those factors was 0.5±0.2%.

Conclusions:
We found a substantial incidence of ATO after contemporary FP-EVT, particularly with scaffold. Hemodialysis and involving popliteal lesion were significantly associated with ATO risk in patients treated with scaffold. The scaffold was safely used in patients without those risk factors of ATO, but a non-scaffolding strategy, including surgical bypass therapy, should be considered for patients with those risk factors.
Abstract 11984: A Novel Pathogenic
Gata6
Variant Identified in a Family With Persistent Truncus Arteriosus, Childhood-Onset Diabetes Mellitus and Spontaneous Intestinal Perforation
Authors: Yasuhara Jun , Manivannan Sathiyanarayanan , Majumdar Uddalak , Gordon David , Myers Katherine , Zender Gloria , McBride Kim L , White Peter , Garg Vidu
Published: June 2023

GATA6 is a member of the GATA family of transcription factors, among which GATA4, 5 and 6 are known to play critical roles during heart development. Pathogenic variants in
GATA6
have been primarily associated with congenital heart disease (CHD) and pancreatic agenesis in humans. Although the phenotypic spectrum associated with pathologic variation in
GATA6
has expanded to include developmental delay along with congenital malformations affecting the biliary system and diaphragm, the full disease spectrum of
GATA6
pathogenic variation and genotype-phenotype correlations are unclear. Here, we report a family where the father had persistent truncus arteriosus (PTA) and three children had CHD, 2 with PTA and 1 with an atrial septal defect. Notably, the father had childhood-onset diabetes mellitus and one child had spontaneous intestinal perforation (SIP). Using exome sequencing, we identified a novel, heterozygous missense variant in
GATA6
(c.1403G>A; p.Cys468Tyr) in affected members. This variant is absent from the gnomAD and ExAC databases and causes a missense change predicted to be damaging by all in silico bioinformatic tools. Sanger sequencing confirmed the exome sequencing results and segregation of this variant.
GATA6
p.Cys468Tyr variant affects the highly conserved zinc-finger domain of GATA6 and impedes its ability to bind DNA. Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, in vitro luciferase assays showed that p.Cys468Tyr mutant protein exhibited significantly decreased luciferase transcriptional activity. Furthermore, immunofluorescence revealed that p.Cys468Tyr mutant demonstrated an impaired localization pattern in the nucleus and induced protein aggregation. Our findings expand the variant and phenotypic spectrum for
GATA6.
Our study highlights that
GATA6
variants can cause not only cardiac and pancreatic malformations but also gastrointestinal abnormalities, including neonatal SIP. Further investigation is needed to define the mechanisms underlying the full phenotypic spectrum associated with pathogenic variation in
GATA6
.
Abstract 12001: An Unusual Case of Necrotizing Acute Pericarditis
Authors: Sharifi Sasha , Chib Anjula , Menon Vivek , jaikumar likhitesh , Volansky Paul , JAGTAP DO MANDAR , George Tara , Thang Sophia , Smith Christopher
Published: June 2023

BACKGROUND:
Acute pericarditis is the most common disorder affecting the pericardium. It accounts for less than 1% of patients who are admitted to the hospital for non-ischemic chest pain and 5% who present to the emergency department with non-ischemic chest pain. The most common etiology of acute pericarditis in developed countries is idiopathic although a pre-disposing viral illness has also been recognized as a common cause. Infectious etiologies in developed countries have been seen with commonly occurring viruses such as coxsackievirus, echovirus, adenovirus and less frequently EBV.

CASE:
We present a 41-year-old man who came in with fevers, rigors, shortness of breath and chest pain. Transthoracic echocardiogram was (TTE) demonstrated a large pericardial effusion without evidence of tamponade. He underwent a diagnostic pericardiocentesis followed by a pericardial window during his initial hospitalization without any complications and was discharged home on NSAIDs and colchicine. Serology results demonstrated positive EBV IgG and Nuclear Antigen, concerning for active EBV pericarditis. Pathology resulted as necrotizing pericardial tissue with diffuse inflammation. The patient was readmitted within 48 hours with worsening shortness of breath and leg edema. Repeat TTE revealed a large recurrent pericardial effusion with right ventricular collapse concerning for tamponade. The patient was ultimately transferred to a tertiary care center for pericardiectomy evaluation.

DISCUSSION:
Ebstein-Barr virus is rarely an etiology of acute pericarditis, much less necrotizing pericarditis. When identified it should raise concern for long term complications such as recurrent pericarditis and tamponade. We believe patients who have evidence of necrotizing pericarditis are at a high risk for constrictive pericarditis and should not only have closer follow while maintaining a low clinical threshold for definitive treatment with pericardiectomy.
Abstract 12019: Educational Attainment is Associated With Cardiac Rehabilitation Enrollment
Authors: Chen Yimin , Garfein Joshua , Swabe Gretchen , Magnani Jared W
Published: June 2023

Introduction:
Cardiac rehabilitation (CR) remains significantly underutilized. We examined the association of educational attainment (EA) with CR enrollment in a health claims database, hypothesizing that individuals with lower EA would be less likely to participate in CR.

Methods:
We employed an administrative database (Optum de-identified Clinformatics® Data Mart) to select individuals with incident events indicating CR eligibility from 2016-2018. We collected demographics (age, sex, race and ethnicity); comorbid conditions (hypertension, diabetes, stroke and those defined by the Elixhauser Comorbidity Index); household income; and CR qualifying event. In multivariable-adjusted logistic regression, we related EA (≤high school diploma; >high school diploma and <bachelor’s degree; ≥bachelor’s degree) to CR enrollment. We examined the association of EA and CR enrollment by race or ethnicity strata.

Results:
In 121,598 individuals eligible for CR, those with lower EA had lower odds of CR participation. Individuals with ≤high school diploma had 39% lower odds (95% Confidence Interval [CI] (35-42%) of enrolling in CR compared to those with ≥bachelor’s degree. The association of lower odds of CR enrollment with lower levels of EA persisted across racial and ethnic strata (
Figure
). Black individuals with ≥bachelor’s degree had similar odds of CR enrollment as White individuals with the same level of education (Odds Ratio [OR] 0.95, 95% CI 0.77-1.17). Hispanic (OR 0.26, 95% CI 0.23-0.28) and Asian individuals with ≤high school diploma (OR 0.25, 95% CI 0.19-0.33) had the lowest odds of CR enrollment compared with White individuals with ≥bachelor’s degree.

Conclusions:
We identified associations between EA and CR enrollment persisting across racial and ethnic strata. Our findings support increased attention to individuals with limited education to improve CR enrollment.
Abstract 12020: Overestimation of the Ischemic Area-at-Risk Despite Partial Resolution of Myocardial Edema Twenty-Four Hours After Myocardial Infarction in Swine
Authors: Rolland Tyler J , Fees Alex J , Weil Brian R
Published: June 2023

Objective:
Accurate delineation of the ischemic area-at-risk (AAR) is essential for precise quantification of tissue salvage following myocardial infarction (MI), but time-dependent changes in tissue composition may influence the AAR when it is measured after reperfusion. Based on evidence that post-MI edema declines 24 hours after reperfusion, we utilized serial contrast-enhanced computed tomography (CT) to determine if this is an optimal timepoint for retrospective assessment of the AAR in swine.

Methods:
Swine (n=7) were subjected to a 75-minute LAD occlusion, during which an initial CT scan was performed to assess the pre-reperfusion AAR. A second CT scan was performed during re-occlusion of the LAD 24 hours later to determine the post-reperfusion AAR. Echocardiography was performed at baseline as well as 1 hour and 24 hours after reperfusion to assess end-diastolic wall thickness (EDWT) as an index of post-MI edema. Infarct size was quantified via post-mortem TTC staining and expressed relative to pre- vs. post-reperfusion AAR values.

Results:
Dynamic changes in EDWT were observed throughout the reperfusion period, consistent with marked edema early after reperfusion and a subsequent decline 24 hours later (
Table; top
). Despite partial resolution of edema 24 hours after reperfusion, a significant ~25% increase in the AAR was observed at this timepoint vs. pre-reperfusion values (
Table; bottom
). As a result, infarct size differed significantly if expressed relative to the pre-reperfusion AAR (91.7 ± 9.2 %) vs. the post-reperfusion AAR (70.9 ± 8.3 %, p<0.01).

Conclusion:
The ischemic AAR is overestimated relative to pre-reperfusion values when measured retrospectively 24 hours after reperfusion, despite partial resolution of myocardial edema at this timepoint. These results illustrate how variability in post-infarction edema may complicate the assessment of relative infarct size and myocardial salvage when the AAR is measured after reperfusion.
Abstract 12033: The IFNb-Gbp7 Pathway Plays an Important Role in Activating Cardiomyocyte Genes
Authors: Wang Xinghua , Baksh Syeda , Pratt Richard E , dzau victor , Hodgkinson Conrad
Published: June 2023

We discovered that reprogramming scar fibroblasts into cardiomyocytes requires activation of innate immunity. Recently, we found that innate immunity exerts its influence on fibroblast to cardiomyocyte reprogramming via the RNA-sensing receptor Rig1. However, the mechanism was not identified. Rig1 activation, whether by classical agonists or via rationally designed RNA molecules, enhanced the efficacy of cardiac reprogramming with cardiomyocyte-specific gene expression increasing by 10 to 50 fold (Actn2, Myh6, Tnni3; N=6; P<0.01) and cardiomyocyte generation increasing 5 fold (N=3, P<0.01). RNA-seq indicated that Rig1 activation in fibroblasts induced IFNβ signaling pathways. To verify a role for IFNβ, knockdown studies were performed. Transfection of fibroblasts with an IFNβ targeting siRNA completely ablated the effects of Rig1 agonists with respect to cardiac reprogramming (N=5, P<0.01). Further studies with specific blocking antibodies and media replacement showed that IFNβ was acting in a paracrine manner. To determine the mechanism whereby IFNβ regulated cardiomyocyte gene expression, we screened a number of candidates identified in the RNA-seq: Ccl5, Ccl10, Gbp5, and Gbp7. Knockdown of Ccl5, Ccl10, or Gbp5 had no effect on the ability of IFNβ to enhance cardiac reprogramming efficacy. In contrast, the ability of IFNβ to enhance cardiac reprogramming was lost in fibroblasts lacking Gbp7 (N=5, P<0.01). To conclude, the IFNβ-Gbp7 pathway plays a critical role in cardiac reprogramming. Manipulation of the IFNβ-Gbp7 pathway may enhance the effectiveness of cardiac reprogramming in vivo.
Abstract 12069: Spectrum and Prevalence of Attention Deficit Hyperactivity Disorder (ADHD) and Intentional ADHD-Directed Pharmacotherapy in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Bains Sahej , Bos Johan M , Giudicessi John , MacIntyre Ciorsti J , Ackerman Michael J
Published: June 2023

Background:
The estimated prevalence of attention-deficit/hyperactivity disorder (ADHD) globally is about 5%. For patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), ADHD-directed stimulant therapy is relatively contraindicated. However, previous studies have shown that use of these treatments is safe for patients with long QT syndrome, a similar genetic heart disease. Whether this is the same for patients with CPVT remains unknown.
Objective:
To evaluate ADHD-directed treatment, outcome, and frequency of CPVT-triggered events in patients with CPVT and concomitant ADHD.

Methods:
A retrospective electronic medical record review of 216 patients with CPVT evaluated in Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic was performed to determine the prevalence of concomitant ADHD and the incidence of CPVT-triggered events in these patients.

Results:
Overall, 14 patients (6%) were diagnosed with CPVT and concomitant ADHD (6 female, average age 19 ± 3 years). At the time of first evaluation, ADHD-directed stimulant therapy was stopped or advised against in 8/14 patients (57%). It was (re)started in 11 patients (79%) following comprehensive evaluation and treatment initiation for CPVT with pharmacologic therapy in 14/14 patients (100%), denervation surgery in 12 (86%), and an implantable cardioverter defibrillator in 4 (29%). Prior to Mayo Clinic evaluation, 10 patients (71%) treated for CPVT had a breakthrough cardiac event, without being on stimulant therapy, while 4 patients (29%) had an event while being treated for both CPVT and ADHD for an average time on stimulant therapy of 6 ± 6 years. Following CPVT treatment optimization and ADHD stimulant (re)initiation, patients have remained event-free for a total of 82 patient years (mean follow-up 6 ± 5 years).

Conclusion:
Among patients with CPVT, the prevalence of ADHD was similar to that in the general population, which can be treated safely and effectively with stimulant therapy. Although the rate of adverse events was low in stimulant-treated patients, physicians should weigh the potential effects of suboptimal treatment of ADHD with the theoretical proarrhythmic risk from stimulant medications on a case-by-case basis.
Abstract 12076: Longitudinal Echocardiographic Analysis of Aortic Valve Stenosis Progression
Authors: Khambhati Jay , Tanguturi Varsha K , Chen Chen , Allard-Ratick Marc , Jamiel Paris J , Picard Michael H , Kolte Dhaval , Yucel Evin , Hung Judy , Passeri Jonathan , Langer Nathaniel , Elmariah Sammy
Published: June 2023

Introduction:
Despite its high prevalence, the rate of progression of aortic valve stenosis (AS) remains incompletely characterized and assumed to be constant across the spectrum of AS severity. Previous studies involve limited number of patients, short follow-up, and focused on more severe stages of AS.

Hypothesis:
The annual rate of AS progression as defined by aortic valve mean gradient (AVMG) increases in magnitude as AS class severity increases.

Methods:
The study cohort included adult patients with native AS from the MGH echocardiography database from 1990 to 2020. Patients were included if AVMG was reported in at least two echocardiograms in mild, moderate, or severe AS stages. Generalized linear mixed models were employed to simultaneously model fixed effects and random effects stratified by AS severity grade. Multivariable models included age, sex, race, dyslipidemia, DM2, kidney disease, LVEF, moderate/severe AI, and AV morphology. A linear model identified risk factors for rapid progression in severe AS.

Results:
In 8,848 patients with 29,513 echocardiograms, baseline mean gradient for mild, moderate, and severe AS was 7.0, 20.9, and 43.0 mmHg, respectively. The annual rate of progression in mild, moderate, and severe AS was found to be 0.3, 1.0, and 4.0 mmHg/year. Female gender and white race increased the rate of AVMG by 0.57mmHg/year and 1.05mmHg/year.

Conclusions:
The progression of AS accelerates with worsening severity of AS. The rate of AVMG progression in severe AS is similar to historically accepted values, but rates are slower for mild and moderate AS. Female gender and white race may be associated with faster progression in severe AS.
Abstract 12079: The Sexual Dimorphism of IgG1 Anti-angiogenic Activity Depends on Y Chromosome Genes
Authors: Argyle Dionne A , Pereira Felipe , Wang Shao-bin , Ambati Jayakrishna , Gelfand Bradley D
Published: June 2023

Section:
Angiogenesis, Vascular Development and Regeneration

Introduction:
IgG1 antibodies possess sexually dimorphic anti-angiogenic activity independent of antigen binding. Mosaic loss of Y chromosome (LOY) is associated with numerous cardiovascular-related diseases, and the male specific region of the Y chromosome (MSY) contributes to hypertension, atherosclerosis, cancer, and male infertility. The biological mechanisms underlying these associations is largely unknown and not fully understood. A better understanding of the role of protein coding genes in the Y chromosome and angiogenesis regulation may lead to a better understanding of these associations and better treatments.

Hypothesis:
The loss of function of genes in the MSY of males impairs the anti-angiogenic activity IgG1 antibodies.

Methods:
MSY transcripts were quantified in human macrophages and primary bone marrow derived macrophages (BMDMs) from C57BL/6J male mice by qPCR. MSY genes were inhibited by siRNAs targeting DDX3Y, KDM5D, and UTY, followed by treatment with a human IgG1 in a chemotaxis assay. Laser photocoagulation-induced choroidal neovascularization (CNV) was performed in male C57BL/6J followed by intravitreous injection of full-length humanized IgG1 antibody along with a cell-permeable siRNA scrambled control or siRNA targeting DDX3Y.

Results:
Male macrophages from human and mouse transcribe multiple Y chromosome genes. Silencing of multiple MSY-encoded genes abrogated the ability of IgG1 to suppress chemotaxis and angiogenesis, rendering male systems to respond similarly to female systems. Male macrophages from DDX3Y knockout mice were also resistant to IgG1 treatment. siRNA targeting DDX3Y suppressed inhibition in male mice.

Conclusions:
The antiangiogenic activity IgG1 antibodies is greatly reduced by antagonizing Y chromosome genes. These studies highlight protein coding genes of the Y chromosome as a potential angiogenesis modulating target responsible for sexually dimorphic responses.
Abstract 12084: Premorbid Physical Activity and Prognosis After Incident Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Mok Yejin , Lu Yifei , Ballew Shoshana , Sang Yingying , Kucharska-Newton Anna , Koton Silvia , Schrack Jennifer , Palta Priya , Coresh Josef , Rosamond Wayne D , Matsushita Kuni
Published: June 2023

Introduction:
Physical activity (PA) is associated with a reduced risk of mortality and cardiovascular disease in the general population. However, it is unclear whether PA level in midlife impacts prognosis after myocardial infarction (MI) in later life.

Methods:
In 1,115 ARIC participants with incident non-fatal MI during ARIC follow-up (mean age 73 [SD 9] years at MI, 54% men, 21% Black), PA prior to incident MI (premorbid PA) was evaluated at visit 1 (1987-89) and visit 3 (1993-95) using a modified Baecke questionnaire; we studied the cumulative PA index scores across these two visits. Total and domain-specific PA (sport, leisure time, and work PA) were analyzed for their associations with mortality, recurrent MI, stroke, and heart failure after MI using multivariable Cox models. Elapsed time between visit 3 and incident MI was on average 11.9 (SD 6.9) years.

Results:
During a median follow-up of 2.0 [IQI 0.03-8.0] years after incident MI, 914 participants (82%) developed a composite outcome. The 8-year cumulative incidence of composite outcome was lower in the highest tertile of premorbid total PA than the lowest tertile (62% vs. 72%, respectively) (
Figure
). When adjusting for MI risk factors, the association was not significant. However, for individual outcomes, higher premorbid total PA was associated with a lower risk of recurrent MI (adjusted hazard ratio [HR] 0.66 [95% CI 0.45, 0.96] for the highest vs. lowest tertile). Results were similar for sport and work PA but not leisure time PA. When we focused on short-term prognosis within one year after MI, both higher total PA and sport PA were associated with lower mortality (HR 0.62 [95% CI 0.43, 0.90] and 0.62 [0.44, 0.89], respectively).

Conclusions:
Greater premorbid PA was associated with better prognosis after MI occurrence, both short-term and long-term post-MI. Our results demonstrate additional prognostic advantage of PA beyond reducing the risk of incident MI.
Abstract 12092: Natural Language Processing to Identify Reasons for Gender Disparities in Statin Use
Authors: Witting Celeste , Zammit Alban , Sarraju Ashish , Ngo Summer , Hernandez-Boussard Tina , Rodriguez Fatima
Published: June 2023

Introduction:
Statins are life-saving medications for patients with atherosclerotic cardiovascular disease (ASCVD), but women with ASCVD are persistently less likely to be prescribed statins than men. This study aims to use Natural Language Processing (NLP) to further elucidate patient and provider factors contributing to this disparity.

Methods:
The study cohort included patients with >2 ASCVD encounters between 2014 and 2021 within a multisite electronic health record (EHR) in Northern California. Data from a random sample of our cohort (N = 942) was manually annotated to develop a benchmark deep learning natural language processing (NLP) approach, Clinical Bidirectional Encoder Representations from Transformers (BERT); 80% of these were used for model training and 20% for testing. After reviewing structured EHR data (e.g. prescriptions, allergies), BERT was used to identify and interpret discussions of statins in clinical notes.

Results:
Of 88,913 patients with ASCVD (mean age 67.8 ± 13.1 years), 35,901 (40.4%) were women. Women were less likely to be prescribed statins (56.6% vs. 67.6%, p < 0.001). Only 18.6% of nonallergic patients without a statin prescription had a mention of statins in unstructured EHR text. Statin use through unstructured text was less likely to be identified among women than men (32.8% vs. 42.6%, p < 0.001). Reasons for statin nonuse did not significantly differ by gender (Figure).

Conclusions:
Women with ASCVD were less likely to be use statins, and this disparity became more pronounced with the inclusion of unstructured data. An NLP approach revealed actionable reasons for statin nonuse. Future studies should leverage these approaches to monitor and track statin adherence by combining structured and unstructured data in real-world populations.