bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 91: Useful Predictor of Responsiveness to Initial Intravenous Immunoglobulin in Kawasaki Disease
Authors: kwak jihee
Published: March 2022

Background and Objectives:
Ten to twenty percent of children with Kawasaki disease (KD) do not respond to initial intravenous immunoglobulin (IVIG) treatment, and if untreated approximately 15% to 25% of patients with KD have complications. The aim of our study is to find more useful predictors of responsiveness to initial IVIG in KD.

Subjects and Methods:
We retrospectively reviewed medical records of 91 children diagnosed with KD at Myong Ji Hospital from March 2012 to April 2014. Laboratory data obtained before and 24 to 36 hours after IVIG treatment were collected, which include hemoglobin level, white blood cell count, proportions of neutrophils, lymphocytes and eosinophils, platelet count, erythrocyte sedimentation rate, C-reactive protein (CRP), creatine kinase (CK), creatine kinase MB (CK-MB) and N[[Unsupported Character - Codename ­]]terminal pro-brain natriuretic peptide (NT-proBNP). Subjects were then divided in to 2 groups, IVIG-responsive and IVIG-resistant.

Results:
Among the 91 patients, 11 patients (12%) required retreatment. By univariate analysis, before-IVIG laboratory parameters of white blood cell count, % neutrophils, erythrocyte sedimentation rate, CRP, sodium, CK, CK-MB and NT[[Unsupported Character - Codename ­]]proBNP were significantly different. In the after-IVIG laboratory parameters, hemoglobin level, white blood cell count, % neutrophils, % lymphocytes, CRP, CK, CK-MB and NT-proBNP were significantly different. While the mean-differences were not statistically significant, fractional change (FC)-CRP and FC-% neutrophils showed significant difference. By multivariate analysis, FC-CRP was confirmed to be an independent predictor for initial IVIG resistance.

Conclusion:
FC-CRP might be a more useful and important value for predicting initial IVIG responsiveness in KD patients than before- and after-IVIG CRP.
Abstract O.15: Multicenter Retrospective Study of the Clinical Course of Kawasaki Disease in Latin American Children
Authors: Salgado Andrea , Ulloa-Gutierrez Rolando , Estripeaut Dora , Luciani Kathia , Del Aguila Olguita , Camacho-Moreno German , Faugier Enrique , Martínez-Medina Lucila , López-Medina Eduardo , Izquierdo Giannina , Beltran Sandra , Gamez Luisa B , Collia Adrian , Franco Lorena , Bueno Nora , Daza Carlos , Vargas-Gutierrez Mariella , Li-Chan Susan , Lara Natalia , Levy Jacqueline , Ellis Alejandro , Hurtado Isabel , Berry Erika K , Tremoulet Adriana H ,   REKAMLATINA-2 Study Group
Published: March 2022

Background:
Little is known about the burden of Kawasaki disease (KD) in Latin America (LA). The LA KD network (REKAMLATINA) was established in 2013 and has 120 physicians in over 85 hospitals in 20 countries. It’s goal is to characterize the epidemiology of KD in LA children, to understand the disease impact, and plan for studies that address the specific needs of LA children with KD.

Methods:
Retrospective review of 437 children 1 echo, worst CA status was evaluated for either the RCA or LAD. IVIG therapy response was classified as resistant (fever ≥38C more than 36 hrs after completion of IVIG), responsive or unknown.

Conclusions:
This is the first multicenter report describing the clinical course and treatment of KD in LA. Differences in the care of KD patients were observed among participating countries, specially regarding obtaining echos at baseline and follow up. Also, KD could be an important cause of antibiotic misuse in LA. More research is needed to describe how KD care in LA is influenced by local and economical factors, the available resources, and to standardize treatment in resource- limited settings.
Abstract O.17: Whole Genome Sequencing of a six-member African American family with two Kawasaki disease-affected siblings identifies novel susceptibility variants
Authors: Kim Jihoon , Shimizu Chisato , Yang Hai , Harismendy Olivier , Truong Hoang Long , Levy Eric , Cimaz Rolando , Burgner David , Yeung Rae S , Khor Chiea C , Davila Sonia , Levin Michael , Kuijpers Taco W , Hibberd Martin L , Ohno-Machado Lucila , Burns Jane C ,   the International Kawasaki Disease Genetics Consortium
Published: March 2022

We performed Whole Genome Sequencing (WGS) of a 6-member African American (AA) family with 2 of the 4 children affected with KD. We identified 6,712,158 unique variants across all 6 individuals. We first analyzed the quartet of mother/father/affected sibs and then compared variants in the 2 affected vs. 2 unaffected sibs. Assuming a recessive inheritance model, we identified 49,591 transmitted candidate homozygous variants exclusively present in both affected sibs compared to their parents. The affected vs. unaffected sibling analysis generated 64,187 candidate homozygous variants exclusive to the affected sibs. The intersection of the two analyses identified 20,943 variants of which 303 - in 117 genes - were predicted to be deleterious. We validated the findings in a cohort of 405 KD subjects and 6,252 normal controls using 4,060,864 imputed genotypes. Association analysis of the imputed GWAS dataset for KD susceptibility using the allelic and recessive tests in PLINK found 438,343 SNPs (nominal P-value < 0.05). Of these, 17 variants in 10 genes were also among the 303 variants from the family analysis. These genes were ANGPT1, AS3MT, C10orf32, CMIP, CNNM2, LRIG2, MMP1, NT5C2, SLK, and TLR6. Of these, ANGPT1, MMP1, and TLR6 have been previously associated with KD. For SLK (serine-threonine protein kinase 2) rs10786779 located in the promoter, the homozygous A allele (risk) genotype showed significantly higher expression (p=0.04) in a cohort of 141 acute vs. convalescent mixed ethnic KD subjects on the Illumina HumanRef-12 V4 BeadChip.

Conclusion:
This is the first analysis of WGS in KD and the first to focus on genetic susceptibility in AA children who are second only to Asian children in susceptibility to KD. This exploratory analysis provides new validated variants that may likely contribute to KD susceptibility in AA children.
Abstract O.19: Fine Specificity Of Natural Regulatory T Cells That Modulate Vascular Inflammation
Authors: Franco Alessandra , Touma Ranim , Padilla Robert L , Tremoulet Adriana H , Sidney John , Sette Alessandro , Burns Jane C
Published: March 2022

Objective:
We recently defined that a critical mechanism of IVIG therapy in KD patients is the activation and expansion of natural regulatory T cells (nTreg) that recognize the heavy constant region (Fc) of IgG1. Lack of circulating Fc-specific nTreg in the sub-acute phase of KD strongly correlates with arterial complications. Notably, Fc-specific nTreg are always detectable in circulation in healthy donors, suggesting their importance in maintaining vascular homeostasis. Here we aim at the characterization of the fine specificity of these nTreg by testing the immunogenicity of synthetic peptides (> 97% purity) 15 amino acid long, overlapping 10 amino acids, spanning the whole Fc protein.

Methods:
To define the immunodominat Fc sequences for nTreg expansion, T cell lines have been established with pools of two consecutive overlapping peptides been generated from PBMC ex vivo from: 1) healthy donors, 2) sub-acute KD subjects (2 weeks after IVIG), and 3) KD subjects that received IVIG 1-2 years earlier. IL-10 secretion and CD4+ CD25high T cell expansion have been the read-outs in these experiments.

Results:
14 peptides have been defined immunogenic in all the 3 cohorts with several peptides recognized by the large majority of the subject studied, including patients with arterial complication that did not respond to the whole Fc protein. The algorithm prediction of the HLA binding affinity of these nTreg peptide epitopes suggests that these immunodominant regions of the Fc protein are promiscous for HLA binding and very good candidate for future therapeutic use.

Clinical relevance of the findings:
Immunodominat Fc peptides are an optimized, low cost alternative to IVIG, potentially capable to overcome the lack of nTreg responses in KD patients that develop arterial complications.
Abstract O.40: Persistent Subacute/Chronic Coronary Arteritis in Kawasaki Disease (KD): Histologic, RNA and Protein Evidence
Authors: Rowley Anne H , Kim Kwang-Youn A , Shulman Stanford T , Baker Susan C , Pink Adam J , Innocentini Nancy , Yang Amy , Pahl Elfriede , Carr Michael , Lingen Mark W , Orenstein Jan M
Published: March 2022

Introduction:
We identified 3 linked KD vasculopathic processes: acute self-limiting necrotizing arteritis, subacute/chronic (SA/C) arteritis and luminal myofibroblastic proliferation, most critically affecting the coronary arteries (CA). SA/C arteritis (lymphocytes, eosinophils, plasma cells) was not previously recognized, and patients with persistent coronary artery aneurysms do not currently receive immunomodulatory therapy after the initial febrile illness.

Hypotheses:
SA/C arteritis in KD CA is a process of dysregulated innate and adaptive immune responses, and markers of inflammation can be detected in the sera of KD patients with persistently inflamed CAs.

Methods:
RNA was isolated from paraffin-embedded CA tissues, and real-time RT-PCR arrays performed on samples passing quality control assays. RNA from KD CA with persistent subacute/chronic arteritis (n=7, 5 mo-several yrs after onset, median age=3 yr) and from CA of childhood controls (n=7, median age=10 mo) was assayed, and dysregulated genes determined (>1.5 fold change and q value <0.05). To identify if dysregulated immune markers were detected in sera of KD children with persistent CA aneurysms, ELISA cytokine array for 400 proteins was performed on sera from 4 KD patients with persistently abnormal CA echocardiograms who were otherwise asymptomatic (3-5 yrs after onset, median age 5 yrs) and 4 age/gender matched healthy childhood controls (median age 5 yrs).

Results:
Ten interferon response genes and 9 Th1/Th2 response genes were upregulated in chronic KD arteritis tissues. ELISA revealed ~40 proteins with at least tenfold dysregulation in sera of KD children with persisting aneurysms compared to matched controls (q-values=0.07), while serum C-reactive protein levels were not different in the 2 groups.

Conclusions:
Evidence of dysregulated immune responses can be detected in KD CA tissues months to years after onset in patients with persistent CA disease. In addition, we identified many candidate immune biomarkers of chronic KD arteritis. An immune biomarker panel would be useful to identify and monitor patients with persistent coronary arteritis in potential future clinical trials of immunomodulatory therapies for such patients.
Abstract O.47: Prediction of IVIG Resistance using Kawasaki Disease Risk Scores and Baseline Coronary Z-Scores at a Single North American Center
Authors: Son Mary Beth F , Kim Susan , Gauvreau Kimberlee , Tang Alexander , Dedeoglu Fatma , Fulton David , Lo Mindy S , Sundel Robert P , Newburger Jane W
Published: March 2022

Aim:
At a single pediatric tertiary care center, we assessed the performance of established Japanese risk scores (RS) to identify patients (pts) with Kawasaki Disease (KD) at higher risk for re-treatment (re-tx). We also sought to determine if the addition of baseline coronary Z-scores to RS could improve the prediction re-tx.

Methods:
We reviewed available clinical, lab and echocardiogram (echo) data for KD pts treated from 1/2006 to 5/2014. The maximum z-score (zMax) of the right coronary artery (RCA) or left anterior descending artery (LAD) at baseline was used. Abnormal coronary arteries at baseline echo were defined as zMax ≥2 in the RCA or LAD. Kobayashi, Sano, Egami and Harada scores were calculated, comparing low and high risk scores to re-tx. The zMax was incorporated into each RS with 1 point added (+1) if baseline zMax ≥2. In an alternative approach, zMax was added as a covariate in a logistic regression model. The discrimination of each model was assessed using the c statistic.

Results:
Of 339 pts, 214 (63%) were male, and median age was 3.2 y (range 0.1-14.1 y). At diagnosis, 29% (97/339) had ≤3 classical criteria for KD, and 25% (85/339) received IVIG re-tx. At baseline, the median zMax was 1.37 (-1.64-14.2) and 26% (88/339) had zMax ≥2. Classification as high risk by all four RS was significantly associated with re-tx (p<0.001-0.02). Baseline zMax <2 vs. ≥2 was also associated with re-tx (50 [21%] vs. 30 [34%], p<0.02). The ORs for re-tx were significant for all RS, but c-statistics were low, with a c statistic <0.7 (range of 0.57-0.61). RS +1 for zMax ≥2 did not improve the prediction for re-tx (c statistic 0.58-0.63). However, the addition of zMax ≥2 as a covariate improved the discrimination of all RS for re-tx (c-statistic 0.6-0.67).

Conclusions:
Published RS for predicting IVIG resistance are associated with higher rates of re-tx in our patient population, but are not sufficient to discriminate patients at risk for re-tx. With the addition of baseline zMax as a covariate to the RS, prediction for re-tx was improved, although still modest. Further study in larger, multi-center studies are needed to validate these findings and to better understand the risk factors for re-tx in KD in North American children.
Abstract O.56: Myocardial Fibrosis in Patients with a History of Kawasaki Disease: a Pilot Study
Authors: Dusenbery Susan M , Newburger Jane W , Gauvreau Kimberlee , Baker Annette , Powell Andrew J
Published: March 2022

Background:
Myocarditis occurs in acute Kawasaki disease (KD), and case series with endomyocardial biopsy report that KD patients (pts) may have myocardial fibrosis. The new cardiac magnetic resonance (CMR) technique of myocardial T1 measurement is a noninvasive means of measuring diffuse myocardial fibrosis. We sought to assess the prevalence and risk factors for diffuse myocardial fibrosis in KD pts using CMR.

Methods:
In this retrospective study, all pts with KD who had a CMR with extracellular volume fraction (ECV) measurement at Boston Children’s Hospital were included. The ECV, a measure of diffuse fibrosis, was calculated in the mid-left ventricle by measuring T1 values for blood pool and myocardium before and after gadolinium with a Look-Locker technique, and adjusting for hematocrit. Myocardium with focal fibrosis as evidenced by late gadolinium enhancement (LGE) was excluded. ECV results were compared to values from control subjects (n=20; median age 16 yrs (range, 11-36)) who had a normal CMR exam, and no history of left heart disease or cardiomyopathy.

Results:
Subjects (n=10) had a median age at CMR of 13 yrs (range, 8-36), median age at KD diagnosis of 3 yrs (0.3-11), and median time interval from diagnosis to CMR of 10 yrs (0.3-34). Nine pts had coronary aneurysms and the other 1 had mild left ventricular dysfunction. All 3 pts with a known history of myocardial infarction (MI) had a LGE pattern consistent with MI. LGE with a MI pattern was also seen in 1 additional pt without a history of MI but who had undergone coronary bypass surgery. Overall, ECV was not significantly different in KD pts and controls (0.25 ± 0.03 (range, 0.21-0.30) vs. 0.24 ± 0.03 (range, 0.18-0.28), p=0.29). One pt (10%) had an increased mean ECV (>0.28). ECV was not associated with indexed LV mass, mass/volume ratio, ejection fraction, or LGE.

Conclusions:
In this small pilot study of KD pts most of whom had aneurysms, diffuse myocardial fibrosis based on ECV did not differ significantly from that in normal control subjects, although 1 in 10 pts had an ECV above the normal range. Future larger studies should compare ECV in KD pts with and without aneurysms to define the risk of myocardial fibrosis after KD and to guide future recommendations for follow-up and therapy.
Abstract O.75: Factors Associated With Illness Impact After Diagnosis Of Kawasaki Disease And Coronary Artery Complications
Authors: Chahal Nita , Jelen Ahlexxi , Rush Janet , Boydell Katherine , Manlhiot Cedric , Sananes Renee , McCrindle Brian W
Published: March 2022

Background:
Families with Kawasaki disease (KD) experience profound anxiety, part of which is related to uncertainties about the future. We sought to understand the personal and emotional impact of uncertainty for both parents and children with coronary artery complications.

Method:
During 2013-14, 31 participants were recruited. Data collection included chart reviews of demographic factors, relevant medical history, investigations, and treatments. Parents and children completed questionnaires (uncertainty, intrusiveness, self-efficacy) and were interviewed. The qualitative data were analyzed for common themes and exemplars in order to complement the quantitative questionnaire data.

Findings:
Descriptive data were compared with questionnaire scores to identify factors associated with high, negative impact using univariable linear regression models. High intrusiveness scores among parents were associated with having a child who had previous cardiac catheterization (p =.05), received anticoagulant medications (p = .04), lower education (p = .02 [mother], p = .04 [father]) and income (p = .05), and for those in whom the KD diagnosis was initially missed (p <.001). Higher uncertainty scores among children were associated with absence of chest pain (p = .04) and lower number of echocardiograms (p = .01). Parents’ uncertainty was associated with missed diagnosis (p = .002), higher education (p = .03 [mother]), and higher income levels (p = .01). Self efficacy was assessed among children >10yrs. While 3 subscales (academic, social, emotional) were analyzed, the overall self-efficacy scores increased with the presence of chest pain (p = .003) and increased aneurysms z-score (p =.03). Qualitative analysis revealed 3 main themes: 1) staying normal while hyper-vigilant; 2) optimism amid relentless worry; and 3) healthy present for a hopeful future. The themes involved contrasting sentiments, each of which was held by the child or the parent but with varied levels of expression.

Summary:
Negative illness impact is associated with a more intense medical experience. Both children and parents have concerns about future outcomes and management. Coping with uncertainty involves achieving a balance between anxieties and a present and forward focus.
Abstract 15863: Prevalence of Platelet Non-resposiveness to Aspirin by Thromboelastography (teg) in Children With Congenital Heart Disease: An Institutional Experience
Authors: Molina Fernando , Ghaleb Stephanie , Gonzalez de Alba Cesar , Bartakian Sergio , Brownlee John
Published: March 2022

Introduction:
Aspirin is used to prevent thromboembolism in children with heart defects. Aspirin resistance has been reported in up to 26% of pediatric patients with cardiovascular defects undergoing surgical procedures with significant inpatient variability noted. Because of a patient who had embolic stroke while on therapeutic aspirin doses but in whom aspirin resistance was present on his thromboelastogram (TEG), we chose to obtain a TEG on cardiac patients on aspirin to assess their risk. This study evaluates aspirin resistance noted in these patients.

Hypothesis:
Aspirin resistance is high in pediatric patients with heart conditions

Methods:
This is a retrospective observational study with IRB approval of 21 patients taking aspirin. Seven Females and 14 males were enrolled, ages 5 months to 27 years. Fourteen had a Fontan surgery. Three had a cavo-pulomanary anastomosis, 1 had HLHS hybrid procedure, 1 had a coronary bypass due to ALCAPA and another had a coronary aneurysm. Aspirin doses were at 5 mg/kg/day but not exceeding 81 mg and had been given at least for one month. Compliance was assured with the patient/family at the time of the clinic visit. Platelet mapping with a TEG was performed on each patient. Aspirin resistance was defined as platelet inhibition below 50%. Variables evaluated were: Level of platelet inhibition(AA plt%),
age
in months,
Weight
in Kg,
gender
and
diagnosis
. Statistical

Analysis:
Chi Square and Pearson Correlation.

Results:
Aspirin resistance was present in 77% of these patients (50% in post Fontan and 66% in the remaining patients). There was no significant variation between
genders
(P 0.576) Correlation between platelet inhibition level for
weight
were R: -0.3233 (P 0.153) and age were R -0.0923 (P 0.69) both not significant.

Conclusions:
The percentage of patients in our group on aspirin with inadequate platelet inhibition is unacceptably high and represents pharmacologic failure based on the TEG. Our findings suggest our cardiac patients may have significantly increased aspirin resistance. A larger cohort is needed to assess if traditional dosing of aspirin for antiplatelet effect is not correct for children.
Abstract 15941: The Effects of Training and Detraining on T Wave Inversion in Athletes
Authors: Malhotra Aneil , Varkey Sneha , Dhutia Harshil , Walker Mike , Narain Rajay , Merghani Ahmed , Millar Lynne , Papadakis Michael , Sharma Sanjay
Published: March 2022

Introduction:
T wave inversion (TWI) is the electrical hallmark of primary cardiomyopathies which are substrates for sudden death in young athletes. Such repolarization anomalies can feature on the ECG of an apparently healthy athlete and pose major diagnostic dilemmas in sports cardiology. Athletes are reluctant to detrain during the season.

Hypothesis:
This study hypothesized that detraining would affect TWI in athletes.

Methods:
Between 2013-2014, 36 professional footballers demonstrated TWI at mid-season ECG screenings (trained period). They were followed up during the "off-season" after a period of detraining (6-8 weeks). TWI was defined as –0.1 mV or greater 2 or more contiguous leads: anterior leads-V2-V3/4; inferior-II,III,aVF; or lateral-beyond V4 +/-aVL.

Comparisons were drawn by 2 independent cardiologists, between trained and detrained ECGs. All players were also investigated for an underlying cardiomyopathy.

Results:
*Athletes were male, aged 24.5+/-2.7 years.

*27 (75%) were Afro-Caribbean and 25% Caucasian (p=0.0141).

*TWI was most common in the anterior leads (n=20, 55%), followed by inferior (n=10, 28%) and lateral (n=6, 17%) as in the bar chart.

*No Caucasian player had TWI laterally.

*After detraining, 16 players demonstrated resolution of anterior TWI (80%, p=0.0293), 8 in inferior leads (80%, p=0.2353) and 4 in the lateral leads (67%, p=0.638) (Figures 1a & b).

*All players with abnormal TWI according to consensus guidelines were evaluated with no cardiomyopathy identified.

Conclusions:
In athletes who detrained during the 'off-season', we observed resolution of TWI in the majority of athletes (both Afro-Caribbean and Caucasian) after a relatively brief period of detraining which may be a physiological phenomenon. This was statistically significant in the anterior leads.

However, TWI in the inferior and/or lateral leads should always raise the suspicion of an underlying cardiomyopathy, especially if persistent after detraining.
Abstract 16190: Subclinical Hyperthyroidism and Risk of Atrial Fibrillation: A Systematic Review and Meta-analysis
Authors: Veerappan Kandasamy Vimalkumar , Saurav Alok , Kaja Ajay Kumar , Alla Venkata Mahesh
Published: March 2022

Introduction:
Overt hyperthyroidism is a well-known risk factor for development of atrial fibrillation (AF). On the other hand, studies assessing risk of AF in patients with subclinical hyperthyroidism (SCH), have reported conflicting results on the directionality and the strength of this association. We therefore systematically reviewed published literature and performed a quantitative analysis to assess the risk of AF in these patients.

Methods:
A comprehensive search of articles assessing the risk of AF in patients with SCH was done in PUBMED and COCHRANE databases through May 2015. SCH was defined as decreased Thyroid stimulating hormone (TSH) level accompanied by normal concentrations of serum thyroid hormone in asymptomatic patients. After screening abstracts, full texts of potentially relevant studies were reviewed independently by two authors. Data was extracted on standardized forms. Meta-analysis was performed using random effects model (DerSimonian Laird). The main measure of association was relative risk with 95% confidence intervals.

Results:
A total of 7119 patients with SCH and 588,839 controls across 4 studies were included in the analysis based on predefined inclusion and exclusion criteria. The relative risk for AF was significantly increased in patients with SCH compared to controls [relative risk: 2.48 (CI: 1.50-4.09; p< 0.001)] during a mean follow up of 5.5 years. There was no significant heterogeneity or publication bias. Sensitivity analysis by exclusion of individual studies had no impact on the summary effect estimate. One study reviewed but not included in the quantitative analysis demonstrated increased risk of AF in patients with low normal TSH compared to mid normal range.

Conclusion:
This analysis demonstrates that the risk of AF is >2 fold higher in the presence of SCH. It remains to be seen whether treatment of these patients before development of overt hyperthyroidism decreases the risk of AF.
Abstract 16226: A Work-sampling Study to Value Stream Map the Door to Groin Process With Magnetic Resonance Imaging Reduces the Door to Revascularization (D2R) Times in Major Acute Ischemic Stroke (AIS)
Authors: Barnett Addison E , Singer Justin , Ray Abhishek , Fussner Julie , Tarr Robert
Published: March 2022

Introduction:
Neurologic recovery following revascularization procedures for major AIS are dependent on the speed and adequacy of reperfusion but core infarct volume predicts the risk of intracranial hemorrhage and malignant edema. MR diffusion-weighted imaging is far more sensitive and reliable than CT in depicting the core infarct but few stroke centers use this for urgent decision-making due to time delays and challenges for patient monitoring.

Hypothesis:
A work-sampling analysis could quickly identify opportunities to reduce D2R times that incorporate sensitive but time consuming neuroimaging.

Methods:
The Lean A3 process defined the current and a future state of AIS patient throughput. Over 2 weeks, a work-sampling study was conducted to identify sources of wasted time that were attributed to manpower, materials, measurement, treatment plan, communication and throughput through a root cause analysis. Cycle time data was collected on all major AIS patients transferred for treatment.

Results:
Structured interviews were conducted with 14 providers and an extensive task analysis obtained by observing 5 AIS patients. Resulting process improvements included 1) Pre-hospital completion of MR safety checklist, pre-registration, and standardization of data paged to team, 2) BAT Leader to delegate tasks and monitor time, guided by a customized flow sheet, 3) Streamlined evaluation and transport with MR-compatible monitors, 4) Strategic investments in travelling RN, MR-compatible IV pump, remote imaging access for consensus decisions. D2R time was reduced by 14% (27 min) from Baseline (191 min, n=20), after implementation of a BAT Neuroimaging Algorithm (178 min, n=14), and after throughput efficiencies (164 min, n=6).

Conclusions:
Work-sampling studies can rapidly improve D2R times in AIS. Efficiency is critical to offset time delays when using MR for safe patient selection; this becomes increasingly important when brain ischemia is prolonged or unknown.
Abstract 16261: Risk of Stroke or Systemic Embolism After Transseptal Ablation in Patients With Implanted Cardiac Devices
Authors: Noseworthy Peter , Madhavan Malini , DeSimone Christopher , McLeod Christopher , Sangaralingham Lindsey , Asirvatham Samuel , Yao Xiaoxi
Published: March 2022

Introduction:
Mobile thrombi are commonly observed on endovascular leads at the time of catheter ablation. Transseptal puncture poses a risk of paradoxical embolism. We sought to examine the risk of stroke or systemic embolism after transseptal ablation in patients with and without cardiac implantable electronic devices (CIEDs).

Methods:
Using a large, national administrative claims database we identified 31,720 patients who underwent a catheter ablation requiring transseptal puncture between 1/1/2004 and 9/30/2014. We created two propensity-matched cohorts, matching on age, gender, race, household income, region, Charlson index, CHADS-Vasc score, and year and indication for ablation (5,533 patients with CIEDs and 11,300 patients without devices). Incidence rates (events/100 patient-years) and propensity score-matched cox proportional hazards models (with 95% confidence intervals) were used to estimate risk of stroke, transient ischemic attack, or systemic embolism for patients with or without CIEDs. We also examined the impact of presence of a CIED and oral anticoagulation (OAC) use on risk of stroke or systemic embolism within the matched cohort. Average follow up was 2.1 years.

Results:
The event rate was 1.5 per 100 person years in patients without device, and 1.9 per 100 person years in patients with device. Among patients not on OAC, presence of a cardiac device was associated with an increased risk of stroke or systemic embolism (HR 1.71 [1.24-2.35], P<0.01) whereas there was no association among patients treated with OAC (0.98 [0.75_1.28], p=ns) (Figure).

Conclusions:
Cardiac devices are associated with an increased risk of stroke or systemic embolism after transseptal ablation, but this risk is attenuated with post ablation OAC use. Anticoagulation should be considered for all patients with CIEDs post transseptal ablation, regardless of the presence of another compelling indication for anticoagulation.
Abstract 16391: Zfp148 Deficiency Reduces Lesional Macrophage Proliferation and Atherosclerosis in Mice by Activating P53
Authors: Sayin Volkan I
Published: March 2022

Introduction:
Cell proliferation and cell cycle control mechanisms are believed to play central roles in the pathogenesis of atherosclerosis. The transcription factor Zinc finger protein 148 (Zfp148) was recently shown to maintain cell proliferation under oxidative conditions by suppressing p53, a checkpoint protein that arrests proliferation in response to various stressors. It is established that inactivation of p53 accelerates atherosclerosis, but whether increased p53 activation confers protection against the disease remains to be determined.

Hypothesis:
We aimed to test the hypothesis that Zfp148 deficiency reduces atherosclerosis by unleashing p53 activity.

Methods and Results:
Mice harbouring a gene-trap mutation in the Zfp148 locus (Zfp148gt/+) were bred onto the Apoe-/- genetic background and fed a high-fat or chow diet. Loss of one copy of Zfp148 markedly reduced atherosclerosis without affecting lipid metabolism. Bone marrow transplantation experiments revealed that the effector cell is of hematopoietic origin. We next investigated whether p53 is part of the underlying mechanism. Peritoneal macrophages and atherosclerotic lesions from Zfp148gt/+Apoe-/- mice showed increased levels of phosphorylated p53 compared to controls, and atherosclerotic lesions contained fewer proliferating macrophages. Zfp148gt/+Apoe-/- mice were further crossed with p53-null mice (Trp53-/-). There was no difference in atherosclerosis between Zfp148gt/+Apoe-/- mice and controls on a Trp53+/- genetic background, and there was no difference in levels of phosphorylated p53 or cell proliferation.

Conclusions:
Zfp148 deficiency increases p53 activity and protects against atherosclerosis by causing proliferation arrest of lesional macrophages. The protective effect is entirely dependent on p53 and suggests that drugs that increase p53 activity may be useful in the treatment of atherosclerosis.
Abstract 16403: Trajectories of Depression and Anxiety Symptoms are Predictive of Physical Health-related Quality of Life, Mortality, and Hospital Admission at 1-Year Among Patients With Heart Failure
Authors: Roser Lynn P , Alhurani Abdullah S , Lennie Terry A , Lee Christopher S , Biddle Martha , Frazier Susan , Fleming Stephen , Moser Debra K
Published: March 2022

Background:
Little is known about the symptom trajectories of depression and anxiety in heart failure (HF) patients and how these symptoms influence health outcomes over time.

Objective:
The goal of this study was to describe unique trajectories of depression and anxiety symptoms in HF patients over 12 months and determine whether changes in these symptoms predict subsequent physical health-related quality of life (P-HRQOL) and event-free survival.

Method:
The study sample consisted of 597 patients with HF enrolled as part of a larger longitudinal study at 8 sites from across the United States. The Patient Health Questionnaire-9, the Brief Symptom Inventory Anxiety subscale, and the Minnesota Living with Heart Failure Questionnaire Physical Subscale were used to assess depression, anxiety, and P-HRQOL, respectively. Latent growth mixture modeling was used to identify distinct trajectories of change in depression and anxiety.

Results:
Three trajectories of depression and three trajectories of anxiety were identified (entropy = 0.919). Trajectory changes in depressive symptoms were labeled as getting better (81.1%), bad and getting slightly worse (13.9%), and bad and getting much worse (5.0%). Trajectory changes in anxiety were labeled as getting better (66.7%), stable with slight improvement (22.1%), and getting much worse (11.2%). The trajectories of depression labeled as bad and getting slightly worse and bad and getting much worse were predictive of a poorer P-HRQOL at one-year than the trajectory which showed improvement (β 11.6, p<0.001 and β 15.6, p<0.001, respectively). Changes in depressive symptoms labeled as bad and getting slightly worse was also a significant predictor of event-free survival (HR = 2.17, p<0.001). The two anxiety trajectories which showed stable, slight improvement and much worse anxiety symptoms over 12-months were significant predictors of worse P-HRQOL (β 12.0, p<0.001 and β 18.7, p<0.001, respectively). The trajectory of anxiety symptoms labeled getting much worse was a significant predictor of event-free survival (HR = 2.18, p<0.001).

Conclusion:
We identified three distinct trajectories for both depression and anxiety symptoms, some of which were predictive of P-HRQOL and event-free survival at one year.
Abstract 16408: Acute Changes in Tricuspid Annular Plane Systolic Excursion and Myocardial Deformation in Fetuses With Twin-twin Transfusion Syndrome After Selective Fetoscopic Laser Therapy
Authors: Yilmaz Betul , Moore Ryan A , Statile Christopher J , Keller Regina , Lim Foong-Yen , Michelfelder Erik C
Published: March 2022

Introduction:
Twin-twin transfusion syndrome (TTTS) is a serious complication affecting 10-15% of monochorionic twin gestations. Right ventricle (RV) function is often abnormal in these fetuses. Tricuspid annular plane systolic excursion (TAPSE) and myocardial strain are used as a marker of RV function in a number of disease processes postnatally.

Hypothesis:
Monitoring TAPSE and myocardial deformation may aid in assessing response to selective fetoscopic laser therapy (SFLP) in TTTS. Our objective was to determine whether TAPSE and myocardial deformation are altered after SFLP.

Methods:
Fetal echocardiograms of 22 recipient (RT) and donor (DT) twin pairs with TTTS were prospectively evaluated. TAPSE was obtained via M-mode through the lateral tricuspid annulus in the vertical 4-chamber (4C) view. 2D 4C views were acquired utilizing high frame rates (>30 frames/sec) and were interrogated offline using feature-tracking software for strain analysis. Global RV longitudinal strain, TAPSE, and myocardial performance index (MPI) were compared pre and post-SFLP. Reproducibility of both TAPSE and RV strain was assessed.

Results:
Initial fetal echo was performed at 20.8 ± 2.3 weeks gestation. Median time between initial study and post-SFLP was 7 days (interquartile range 1 to 11 days). DT showed a slight improvement in strain, but not in TAPSE post-SFLP (Table). There was a significant, acute improvement both in global longitudinal strain and TAPSE among RT after SFLP (Table). Interobserver variability for TAPSE and strain was 4% vs 36%, respectively.

Conclusion:
After SFLP, there is an acute improvement in the global RV strain and TAPSE in RT, consistent with improved RV long-axis function or loading conditions. TAPSE is feasible in most fetuses, and is considerably more reproducible than myocardial strain. Further work examining the relationship between RV function and outcome post-SFLP is warranted in TTTS population.
Abstract 16419: Epigenetic Readers: An Attractive Way to Tackle PAH and the Associated Vascular Comorbidities
Authors: Meloche Jolyane , Potus Francois , Vaillancourt Mylene , Bourgeois Alice , Breuils-Bonnet Sandra , Provencher Steeve , Bonnet Sebastien
Published: March 2022

Introduction:
Pulmonary arterial hypertension (PAH) is a devastating vasculopathy. Recent progress in understanding its pathogenesis led to an increase in patients’ quality of life. With ageing, PAH patients now develop comorbidities including coronary artery diseases (CAD), further challenging their therapeutic management. We previously reported that CAD and PAH share many similarities, including vascular smooth muscle cells (VSMCs) pro-proliferative/anti-apoptotic and metabolic abnormalities. We could speculate that PAH and CAD development share many pathophysiological pathways. In cancer, the epigenetic reader Bromodomain-containing protein 4 (BRD4) increases transcription of many oncogenes contributing to the proliferative/apoptosis imbalance. Interestingly, BRD4 was shown to interact with miR-204 and NFAT, both critical players in PAH and CAD. We hypothesized that BRD4 is a central actor of VSMCs impairment contributing to vascular remodeling observed in PAH and CAD.

Method/Results:
We demonstrated that remodeled distal pulmonary arteries from PAH patients exhibit a miR-204-dependent increase in BRD4 expression compared to controls (qRT-PCR, western blot, n=10-15, p<0.01). This phenotype is also observed in VSMC of remodeled coronary arteries from both PAH patients with CAD and non-PAH CAD patients compared to non-CAD patients (n=10, p<0.05). In vitro, we showed that BRD4 increases NFAT, Bcl-2 and Survivin (n=6, p<0.01) expression, triggering both proliferation (Ki67, p<0.05) and resistance to apoptosis (AnnexinV, p<0.05) while decreasing spare respiratory capacity (Seahorse XF, n=4, p<0.05) and hyperpolarizing mitochondrial membranes (TMRM, p<0.05). All these abnormalities were reversed upon BRD4 inhibition (JQ1 or siBRD4). In vivo, JQ1/siBRD4 reverses established PAH and prevents carotid stenosis in Sugen/hypoxia and carotid injury rat models respectively (n=8-10/group).

Conclusion:
Comorbidities in PAH such as CAD has become a major clinical problem. Thus, targeting mechanisms implicated in both PAH and subsequent comorbidities is warranted. To this aim, we propose that BRD4 might represent an attractive target and since BRD4 inhibitors are presently in clinical trials further potentiates its uses in PAH.
Abstract 16420: The E3 Ubiquitin Ligase is Upregulated During Cardiac Hypertrophy
Authors: Basheer Wassim A , Price Robert L , Spinale Francis G , Matesic Lydia E
Published: March 2022

Introduction:
Cardiomyocyte hypertrophy is observed during normal postnatal cardiac development as well as during disease-related cardiac remodeling. This growth is accompanied by dynamic changes at the intercalated disc, including the redistribution and degradation of the gap junction protein connexin 43 (Cx43). We have shown that the ubiquitin ligase Wwp1 can promote the degradation of Cx43, and that genetic upregulation of Wwp1 stimulates hypertrophy and arrhythmogenesis.

Hypothesis:
We hypothesized that changes in the expression of Wwp1 would be associated with developmental and pathological hypertrophy programs.

Methods:
Expression of Wwp1 was analyzed by digital droplet PCR in hearts derived from normally developing mice at 2, 4, 6, and 8 weeks of age (n=6 for each) or from adult mice subjected to transverse aortic constriction (n=5) vs. sham operated animals (n=5). Cardiac structure and function of mice overexpressing or lacking expression of Wwp1 was evaluated by transmission electron microscopy (n=3) and echocardiography (n=6).

Results:
The expression of Wwp1 during postnatal development was very dynamic, peaking at a concentration of 324 copies/uL in the hearts derived from 4 week old animals. This also corresponded to the timepoint when the gap junction length at the intercalated disc plateaued. Further, a 1.5-fold increase in the expression of Wwp1 in animals subjected to pressure overload was detected as compared to animals subjected to surgery without pressure overload (p<0.007). Interestingly, the concentration of Wwp1 message in pressure overloaded animals (331 copies/uL) was nearly identical to that found in 4 week old wild type animals during normal postnatal development. Consistent with the level of Wwp1 correlating with cardiomyocyte hypertrophy, animals lacking Wwp1 had a 23-42% decrease in left ventricular mass (p<0.01) whereas transgenic animals overexpressing Wwp1 had a 28-50% increase in left ventricular mass (p<0.005) as compared to wild type controls between 4 and 8 weeks of age.

Conclusions:
This study shows that expression of Wwp1 is upregulated during hypertrophy and this correlates with ultrastructural changes at the intercalated disc.
Abstract 16429: Neuro-endocrino-immunological PBMC Signatures Early After Mechanical Support Device Implantation
Authors: Starling Charlotte , Cadeiras Martin , Chang Eleanor , Bondar Galyna , Wisniewski Nicholas , Bakir Maral , Shubov Andrew , Zhou Wei , Liem David , Deng Mario
Published: March 2022

Background:
The neuro-endocrino-immunological (NEI) pathophysiology associated with advanced heart failure (AdHF) progression and arrythmogenesis is not well understood. While it has been shown that mechanical circulatory support device (MCSD) implantation rapidly restores normal hemodynamics, it is unknown as to whether NEI mechanisms also normalize rapidly. We hypothesized that transcriptional activity in PBMC reflecting NEI normalizes shortly after MCSD implantation.

Methods:
We collected PBMC samples from 25 MCSD patients and 4 healthy controls (CTRL). Samples were obtained at 1 day before, and 1, 3, 5 and 8 days after MCSD. Purified mRNA was subjected to whole-genome NGS analysis. Statistically significant genes, dysregulated between AdHF patients and CTRLs, were subjected to time dependent bioinformatics analysis.

Results:
We identified 1226 dysregulated gene-transcripts between AdHF patients and CRTLs at baseline. Time dependent analysis provided 344 dysregulated transcripts in AdHF patients across all time-points. An analysis of enriched molecular pathways by dysregulated genes showed 52 pathways with NEI annotations at baseline. The Endothelin pathway, one of the most significant of the 52 pathways, had 17/60 dysregulated transcripts in AdHF patients at baseline and through day 8 after implantation (Fig.1A). Within the Endothelin pathway we found that expression of EDNRB, a gene central to ET1 clearance and ECE-inhibition, is persistently elevated through day 8 after MCSD (Fig.1B).

Conclusion:
Transcriptional NEI dysregulation is persistent in PBMC 8 days after MCSD implantation. Neuromodulatory strategies targeted at NEI dysregulation and implemented after MCSD implantation may be a mechanism to improve perioperative outcomes. Further studies including validation methods to objectively assess NEI activity are warranted.
Abstract 16531: Acute Hyperglycemia Polarizes and Myocardial Infarction Amplifies Differential Profiles of Gene Expression in Circulating Leukocytes
Authors: Smith Robert S , Piras Bryan A , Farber Charles R , Yang Zequan , Kron Irving L , French Brent A
Published: March 2022

Introduction:
Acute hyperglycemia during MI is associated with higher clinical mortality and increased infarct size in the mouse model of reperfused MI. We used microarray analysis to compare gene expression in leukocytes isolated from normal and hyperglycemic mice after sham surgery or reperfused MI.

Methods:
Four treatment groups of n=4, 12 wk male C57Bl/6 mice were studied: euglycemic sham (EuSS) & hyperglycemic sham (HySS) surgery, and euglycemic MI(EuMI) & hyperglycemic MI (HyMI). Hyperglycemia was induced by 20% dextrose (10mL/kg) IP 20 min prior to MI. MI consisted of 30 min coronary occlusion with 2 h of reperfusion, after which mRNA was isolated from whole blood. Gene profiling was done on Illumina BeadChips using the iScan system. To verify expression patterns, 8 differentially-expressed genes were analyzed by qPCR (n=3/group).

Results:
Differences in gene expression were detected between EuSS, HySS & EuMI mice, but none of these comparisons reached significance (all FDR ≥ 0.47). However, the EuMI vs HyMI comparison revealed a significant number of genes that were differentially regulated (241 with FDR < 0.05). Differences between EuSS & HySS expression were amplified (and became significant) only after MI (i.e., in the comparison between EuMI & HyMI mice: Panel A). The 8 genes analyzed by qPCR were found to have a correlation of R2=0.94 with BeadChip fold change data. These genes also exemplified the pattern of gene expression under hyperglycemic conditions that became more pronounced following MI (Panel B). HEFalMp network analysis identified genes from the set of 241 with FDR < 0.05 involved in regulation of T cell activation & differentiation, calcium ion homeostasis, and signal transduction (p < 0.05 for all).

Conclusions:
Hyperglycemia imparts changes in the patterns of gene expression that are amplified by MI. This altered immune response may underlie the larger infarcts in hyperglycemic mice and may contribute to higher mortality in patients with MI.
Abstract 16534: Remodeling of Intimal Matrix by C. Pneumoniae-infected Macrophages
Authors: Evani Shankar J , Dallo Shatha , Ramasubramanian Anand K
Published: March 2022

Introduction:
Chlamydia pneumoniae,
an intracellular pulmonary pathogen, is considered an important risk factor for atherosclerosis through the mechanisms is poorly understood. Infected monocytes from the lung enter atherosclerotic foci, and create a pro-inflammatory environment in the intima. Here, we tested the hypothesis that
C. pneumoniae
infection contributes to intimal matrix remodeling using a 3D model.

Methods:
Primary human monocytes infected with
C. pneumoniae
(either live of heat-killed organisms) at an MOI-1 were embedded in type I collagen matrix. Between 1 to 9 days, we analyzed the kinetics of MMP and cytokine release, cell migration, and structural and mechanical characteristics of the matrix by ELISA, microscopy and rheometry, respectively – with or without specific inhibitors of molecular mechanisms. All experiments were performed with at least 3 donors in triplicates; and statistical significance was assessed by Student’s
t
-test or ANOVA.

Results:
We observed that the infection of macrophages encapsulated in a 3D collagen matrix promote: (i) the production of MMP and pro-inflammatory cytokines; (ii) the remodeling process including degradation, aggregation and realignment of fibers (Fig. A); (iii) an increase in macrophage podosomal extensions and microenvironmental interactions; (iv) the collective, coordinated migration of macrophages to form focal clusters (Fig. B); and (v) an increase in the elastic modulus (Fig. C). We observed that these changes were more pronounced in live than in heat-killed infection. Further, inhibition of MMP, chemotactic stimuli and cell migratory signaling attenuates matrix remodeling.

Significance:
Our results provide novel insights into the role of infection and the mechanisms in modulating atherosclerotic progression, which may provide an attractive new approach to not only test the infectious burden hypothesis but also for the prevention and/or treatment of cardiovascular diseases.