bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13624: Rates of Depression, Anxiety and Stress in Parents of Children With Congenital Heart Disease Using the DASS
Authors: Lee Brian , loomba rohit S
Published: April 2022

Introduction:
There have been many studies investigating the rate of mental health disorders for caregivers of children with congenital heart disease (CHD) but the types and timing of evaluation vary. The Cardiac Neurodevelopmental Outcome Collaborative recommends using the Depression Anxiety Stress Scale (DASS) to evaluate parents between 6-36 months of age. The DASS is a self-completed questionnaire that evaluates for depression, anxiety and stress. There has not been a study investigating the use of DASS in parents of children with CHD.

Hypothesis:
Our hypothesis was that DASS scores would peak initially and improve with time.

Methods:
This study was a single centered, retrospective review from January 1, 2018 to June 1, 2020. Eligible subjects were parents of CHD patients seen in our Neurodevelopmental clinic who completed the DASS. Demographic data, clinical history of the child and DASS scores were recorded. Cox-regression analysis was conducted using a composite end point of having an abnormal score in any of the three DASS domains, depression, anxiety or stress. Data for mothers and fathers were analyzed separately.

Results:
273 mothers and 139 fathers were enrolled. For mothers, elevated scores in each domain were increased at the 12 and 24 months appointments. For fathers, scores for each domain were elevated initially, followed by a decrease before peaking later on. Paternal scores for depression were increased at 36 months and paternal scores for anxiety and stress were increased at 30 months. Increased length of stay for the index surgery was associated with an abnormal DASS score for mothers (B 0.02, p< 0.01) and fathers (B 0.01, p=0.04). Being in a relationship with the father (B -0.8, p<0.01) was associated with freedom of an abnormal DASS score for mothers.

Conclusions:
Abnormal DASS scores peak at different time points for mothers and fathers. These time points may be critical time points to offer social support for parents. In addition, increased length of stay for the child’s index surgery and the parents being in a relationship are important factors in the development of mental distress in parents.
Abstract 13627: Increasing Trend of Cannabis Use Disorder Among Young Patients Admitted Due to Acute Myocardial Infarction
Authors: Desai Darshi , Rahim Naima A , Gadaga Cecilia , Sampath Shrikanth , SHARMA SHILPI , Abdella Bahredin , Patel Krupa , Desai Saral , Theli Abhinay , Patel Achint , Mansuri Zeeshan
Published: April 2022

Introduction:
The prevalence of cannabis use disorder (CUD) has increased in the US especially following its legalization in various states. Few studies have reported that CUD has been associated with increased Acute Myocardial Infarction (AMI) especially in the younger population. There are limited epidemiological studies that estimate the recent trend of AMI among young patients with CUD.

Hypothesis:
To estimate the hospitalization trends of AMI with concurrent CUD and characteristics associated with it in the young population.

Methods:
Study cohort was derived from the National Inpatient Sample (NIS) for the years 2007-2018. Hospitalizations due to AMI among the age group of 18-49 and concurrent CUD were identified using previously validated ICD-9-CM/ICD-10-CM. We then utilized the Cochran Armitage trend test and multivariable survey logistic regression modeling to analyze temporal trends and predictors of CUD among AMI patients.

Results:
Out of a total 819,354 hospitalizations due to AMI among the age group of 18-49 years, 33,488 (4.1%) had concurrent CUD. Hospitalizations due to AMI with concurrent CUD increased from 1722 (2.4%) in 2007 to 4455 (6.7%) in 2018 with a 12% yearly rate (OR 1.1; 95%CI 1.1-1.1; p<0.01). AMI patients with CUD were younger (20.2% vs 7.3%; p<0.01), male (78.1.2% vs 71.6%; p<0.01) and African American (35.2% vs 15.8%; p<0.01). In multivariable regression analysis, age 18-34 (OR 2.9; 95% CI 2.7 - 3.1; P<0.01), male (OR 1.5; 95%CI 1.4 - 1.6; p<0.01), African American (OR 2.5; 95% CI 2.4-2.7, p<0.01), Lower socio-economic status (OR 1.3; 95% CI 1.1-1.4, p<0.01), West region (OR 1.3; 95% CI 1.2-1.5, p<0.01), depression (OR 1.2; 95% CI 1.1-1.3, p <0.01), alcoholism were associated with higher odds of CUD and AMI. Moreover, AMI patients with CUD were more likely to be admitted during the weekend (OR 1.1; CI 1.1-1.1, p <0.01).

Conclusions:
Our study highlights the increasing trend of AMI hospitalizations with concurrent CUD. Our study also identifies that 18-34 years of age, male gender, African American and psychiatric conditions were significant determinants of CUD in young AMI patients. This warrants additional research to prove causal association between CUD and AMI in the young population in the era of increased cannabis legalization.
Abstract 13628: Cardiovascular Toxicity Associated With Vascular Endothelial Growth Factor Receptor Inhibitors Use in Oncology: A Network Meta-Analysis of Phase 3 Clinical Trials
Authors: malik saad ullah , Malik Asad Ullah , Ezeh Ebubechukwu , Kachynski Yury , Nwanwene Kemnasom , Akhigbe Esiemoghie , Hamilton Mackenzie , Quadri Ameer , Nogot Russell , Tirona Maria Tria , Thompson Ellen
Published: April 2022

Introduction:
Which vascular endothelial growth factor receptor inhibitor (VEGFRi) is less cardiotoxic compared to others in same class is not well known. We compared cardiovascular safety profile of all FDA approved VEGFi used as chemotherapy for cancers.

Methods:
We performed PRISMA compliant literature search on PubMed, Embase, Cochrane, Web of Science, Scopus and Clinicaltrials.gov (inception-6/12/2021). Only phase 3 RCTs were included. Primary outcomes were hypertension (HTN), myocardial infarction (MI), heart failure (HF), conduction abnormalities, dyspnea and pedal edema. Random-effects meta-analysis (MA) was conducted followed by frequentist network meta-analysis (NMA). Results were reported as RR with 95% CI and OR with 95% credible intervals (CrI). Quality and risk of bias assessment were done using GRADE and Cochrane risk of bias assessment tools respectively.

Results:
This analysis included 20426 patients from 32 RCTs. There was a very high risk of HTN associated with VEGFi compared to placebo (RR: 4.36, 95% CI:3.5-5.4, I2:69%, p-value:<0.05). Among VEGFi, lenvatinib was associated with slightly higher risk of HTN (Figure 1). There was no difference between VEGFi and placebo in risk of MI (RR: 1.25, 95% CI:0.86-1.83, I2:0%, p-value:0.48), conduction abnormalities (RR: 2.49, 95% CI:0.54-11.58, I2:37%, p-value:0.19), HF (RR: 1.24, 95% CI:0.52-2.93, I2:40%, p-value:0.18), dyspnea (RR: 1.16, 95% CI:0.95-1.43, I2:27%, p-value:0.22) and pedal edema (RR: 3.1, 95% CI: 0.86-11.23, I2:70%, p-value:0.01). Same was true when VEGFi were compared (Figure 2). Risk of bias was low and studies were of moderate to high quality.

Conclusions:
VEGFi are associated with significantly higher risk of HTN compared to placebo. Among VEGFi, Lenvatinib is associated with slightly higher risk of HTN and there is no difference in risk of MI, HF, conduction abnormalities, dyspnea and pedal edema among VEGFi. Study is limited by heterogeneous patient population.
Abstract 13630: Impella Alone vs Intra-Aortic Balloon Pump Plus Impella in Cardiogenic Shock Patients Undergoing Percutaneous Coronary Intervention: Two Are Better Than One?
Authors: Bhuiyan Md , Bimal Tia , Haggerty Greg , Gandotra Puneet , Selim Samy , Ong Lawrence , Gruberg Luis
Published: April 2022

Background:
Cardiogenic shock (CS) is still one of the leading causes of cardiovascular mortality despite advances in therapeutic options. Aggressive management with percutaneous coronary intervention (PCI) and the use of mechanical circulatory support (MCS) devices has been associated with improved survival. The most frequently used MCS devices are the intra-aortic balloon pump (IABP) and the axial flow pump (Impella).

Aim:
To assess in-hospital bleeding complications and outcomes in CS patients treated with either Impella alone vs. IABP combined with Impella while undergoing PCI.

Methods:
Between 12/2010 and 03/2018 a total of 62 CS patients underwent PCI with Impella (n = 33) or IABP and Impella combined (n =29) at 6 hospitals in our system. Bleeding complications were classified according to the Bleeding Academic Research Consortium (BARC). BARC Type 4 (coronary bypass grafting-related) and Type 5 (fatal) bleeding events were excluded. Chi square was used for categorical values and t-test for continuous variables. P<0.05 was considered significant.

Results:
Clinical characteristics, bleeding complications and in-hospital outcomes are shown in the Table. There was a trend towards a higher percentage of STEMI patients treated with both devices. There was a significant higher rate of BARC 2 bleeding events in patients treated with both devices (6% v 28%, p=0.02) and a higher rate of BARC 3 bleeding events in patients treated with Impella alone (70% v 38%, p=0.01). Both groups had high rates of acute kidney failure and acute neurological events.

Conclusions:
In a limited series of CS patients undergoing PCI: 1) the use of Impella alone was associated with a significantly higher rate of BARC 3 major bleeding events; 2) patients treated simultaneously with both devices had a significantly higher rate of BARC 2 bleeding events; and 3) in-hospital acute neurological events and mortality rates were very high but similar in both groups.
Abstract 13816: Real-World Impella Complications in Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Meta-Analysis
Authors: Tung Monica L , O'Brien Connor , Klein Liviu , Cheng Richard
Published: April 2022

Introduction:
Mechanical support devices such as the Impella are increasingly used to support patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) with observational evidence suggesting earlier use improves survival. However, complications associated with Impella including significant bleeding, hemolysis, vascular injury, limb ischemia and stroke are recognized but poorly quantified in this population outside of a small randomized experience.

Methods:
We performed a systematic MEDLINE search to select studies where Impella devices were used in AMICS. Pooled estimates of complications and study heterogeneity were calculated.

Results:
We included ten studies published between 2014 and 2020 with a total of 1037 patients. The median duration of Impella support ranged from 24 hours to 4.6 days. Overall survival to discharge or 30 days was 50% (range 36 % - 66%). Bleeding requiring transfusion occurred in 19.6% (95% confidence interval [CI], 15.2% - 24.8%) and hemolysis in 12.0% (95% CI, 9.0 -15.9%). Both analyses had significant study heterogeneity. Less common were vascular complications requiring surgery in 6.3% (95% CI, 2.8 - 10.2%), bleeding requiring intervention occurred in 4.8% (95% CI, 3.3% - 6.8%), limb ischemia in 4.3% (95% CI, 2.7% - 6.6%) and stroke 2.8% (95% CI, 1.8-4.3%). Two studies did not find significant differences in complication rates comparing Impella use before or after PCI.

Conclusions:
Use of Impella in AMICS is associated with significant morbidity. Real-world complication rates are however reassuringly similar to rates in the randomized experience. With increasing early use of Impella devices in acute MI complicated by CS, clinicians should be aware of these risks to allow for implant optimization, appropriate patient selection, and surveillance for complications. Further investigations are needed to understand clinical correlates of these complication rates.
Abstract 13826: Automatic Aorta Segmentation in Positron Emission Tomography Computed Tomography Using a 3D U-Net
Authors: Van Praagh Gijs , Nienhuis Pieter H , Reijrink Melanie , Spottiswoode Bruce S , Gao Fei , Prakken Niek , Mouridsen Kim Beuschau , Sinha Bhanu , Borra Ronald , Slart Riemer
Published: April 2022

Introduction:
Noninvasive imaging techniques play a central role in identification, stratification, and follow-up of infectious and inflammatory vascular disease. Manual or semi-automatic quantification of these diseases is time consuming. Besides that, most fully automated analysis software fails to integrate information obtained from hybrid nuclear medicine images like PET/CT. The aim of this study is to develop an accurate, fast, and fully automated algorithm to segment the aorta on low dose CT (LDCT) as a navigator for PET-assessed vascular disease.

Methods:
Eighteen non-contrast LDCT scans from [
18
fluor]fluordeoxyglucose ([
18
F]FDG) PET/CT scans were used. The aorta was manually delineated from aortic valve to iliac bifurcation and used as ground truth. Split, rotation, and noise addition augmentation was used on fifteen scans to create 100 3D patches, which were split into a training (n=80) and validation (n=20) set. Three scans were used as test set. Cropping, normalization, and zero-centering were used for image preprocessing to speed up and improve accuracy of the training. No down sampling was used. A U-Net architecture was modified to process 3D inputs and outputs. The Dice Similarity Metric (DSM) was used to assess algorithm performance.

Results:
Fully automated segmentation of the aorta was feasible training a modified 3D U-Net on non-contrast LDCT obtained from PET/CT scans. The test set yielded a DSM of 0.846 ± 0.020 (mean ± SD) for the entire aorta. The run time for the test set with the trained 3D U-Net was on average 2 seconds per patient, whereas the manual delineation was in the order of 30 minutes per patient.

Conclusions:
Comparisons of ground truth and automatic segmentations using the trained 3D U-Net demonstrated excellent concordance. This method can be used for faster and more in-depth analyses of PET tracer uptake in the vascular wall and potentially applied for fast and accurate quantification of inflammatory and infectious vascular diseases.
Abstract 13829: Association Between E-wave Propagation Index and Left Ventricular Thrombus Formation in Systolic Heart Failure
Authors: Bjerregaard Caroline L , Sengelov Morten , Jorgensen Peter G , Bruun Niels , Fritz-Hansen Thomas , Mittal Rajat , Biering-Sørensen Tor , Olsen Flemming J
Published: April 2022

Background:
The E-wave propagation index (EPI) is a measure of apical blood flow and has been proposed as a risk marker of left ventricular thrombus (LVT) formation. We sought to investigate the association between EPI and LVT in patients with heart failure with reduced ejection fraction (HFrEF).

Methods:
This was a retrospective cohort study of patients with HFrEF. Follow-up echocardiograms were investigated for development of LVT. EPI was measured at baseline investigation as the velocity time integral of the transmitral E-wave divided by the left ventricular length. Logistic regression was used to investigate the association between EPI and LVT. Multivariable adjustments were made for age, significant mitral regurgitation, apical aneurysm, prior myocardial infarction, and left ventricular ejection fraction (LVEF).

Results:
Of 785 patients, 24 (3%) developed LVT. Mean age was 66 years, 73% were men, and LVEF was 28%. Those who developed LVT had significantly lower EPI (1.12 vs. 1.36, p=0.02). EPI was significantly associated with LVT in univariable logistic regression (OR=1.16 (1.03-1.31), per 0.1 decrease) (figure). These findings were unchanged after multivariable adjustments (OR=1.15 (1.00-1.31), per 0.1 decrease). The EPI provided an area under the curve of 0.68 with an optimal cutoff of 1.2. This cutoff had a sensitivity of 75%, specificity of 60%, positive predictive value of 6%, and negative predictive value of 99%. A low EPI was associated with a more than 4-fold increased risk of LVT (OR=4.56 (1.79-11.62), p=0.001).

Conclusion:
Decreasing EPI is associated with a higher risk of LVT. While a low EPI poses a markedly increased risk of LVT, a high EPI may be used to rule out LVT.
Abstract 13863: Incidence and Clinical Significance of Cardiac Arrhythmias During Labor
Authors: Sharma Nikhil , Coleman Kristie , Gurciullo Dillon , Ma Rosaline , Hentz Roland , Fishbein Joanna , Shah Nirav , Mountantonakis Stavros
Published: April 2022

Introduction:
Physiologic changes during pregnancy can predispose mothers to new-onset cardiac arrhythmia. Women with a history of cardiac arrhythmia are at increased risk of recurrence or worsening of previously identified conditions. Previous studies have demonstrated that women with heart disease are at increased risk of maternal morbidity and mortality. However, few studies have explored the prevalence and clinical significance of maternal arrhythmias specifically.

Objectives:
The objectives of this study are to define the prevalence of arrhythmias in pregnancy and labor, identify risk factors for having such arrhythmias in patients both with and without prior history of cardiac arrhythmia, and examine the association between cardiac arrhythmias and adverse maternal outcomes.

Methods:
The medical records of patients admitted for delivery to any of the 13 hospitals in Northwell Health utilizing the electronic medical records from Jan 2012 - Dec 2020 were reviewed to identify patients with a history or current diagnosis of cardiac arrhythmia. Outcomes including Cesarean section, length of stay (LOS), infant requiring care in the neonatal intensive care unit (NICU) were evaluated between the arrhythmia group and a subset of deliveries without arrhythmias (controls).

Results:
Out of 141,772 patients, 88 were identified with a history of and/or current SVT and 87 were compared with 334 controls. The sample had mean age 31.7 ± 5.2 years, median length of stay 3 days (IQR 2-3), and median parity 2 (IQR 1-2). When adjusting for age and parity, logistic regression showed SVT was significantly associated with C-section (OR 1.9, CI 1.1-3.1, AUC 0.69 p=0.01). Fisher’s exact test showed SVT was associated with admission to NICU (p=0.03). Cox proportional hazards regression found SVT was not associated with LOS (HR 0.8, CI 0.6-1.0, p=0.06) when adjusted for age and parity.

Conclusion:
A history of SVT and/or current SVT during labor was associated with C-sections and NICU admissions but was not associated with LOS. These findings may help guide treatment strategies for this patient population.
Abstract 14001: Using the S2 Sound as an Early Marker of Aortic Valve Calcification
Authors: Dargam Valentina , Ng Hooi H , Nasim Sana , Iansen Irion Camila , Seshadri Suhas , Shehadeh Lina A , Hutcheson Joshua
Published: April 2022

Introduction:
Heart valve diseases (HVDs) often remain undiagnosed until late stages, especially in underserved populations, leading to significant comorbidities. Artificial intelligence has improved murmur detection in digital phonocardiograms (PCG). However, the presence of murmurs depends on hemodynamic factors unrelated to HVD. Screening tests that directly measure features of valvular remodeling regardless of symptoms would improve HVD diagnosis. We used a mouse model of chronic kidney disease (CKD) induced aortic valve (AoV) remodeling to determine whether S2 sound changes can be used to detect early stages of AoV calcification.

Methods:
Eight-week old C57BL/6J mice (n=24) were assigned the following diets for 12 weeks: 1) control group fed a normal chow diet, 2) CKD group fed an adenine-supplemented diet to induce CKD, and 3) CKD+HP group fed the CKD diet for 6 weeks, then an adenine and high phosphate (HP)-supplemented diet for another 6 weeks to induce AoV calcification. PCG signals were recorded every 6 weeks. Endpoint AoV calcification and echocardiogram measures of valvular function were assessed. We developed a clustering method based on time domain principal component analysis of S2 sounds collected at week 6 (W6) to classify week 12 (W12) S2 sounds and identify S2 sound alterations due to HP.

Results:
The high phosphate diet induced AoV calcification in CKD+HP mice (1a). Of the total number of S2 sounds per mouse, an average of 84.18% and 81.15% S2 sounds (1b and 1c) were accurately classified as control or CKD mice with a specificity and sensitivity of 90.91% and 100%, respectively. CKD+HP mice had an average of 59.22% W12 S2 sounds that neither classified as control nor CKD.

Conclusions:
Mice that have AoV calcification show distinct S2 sounds features that were absent in the control and CKD groups. In this study, we demonstrate the feasibility of using the S2 sound not only to detect AoV calcification prior to expected hemodynamic changes but also to detect CKD.
Abstract 14011: Myomegalin, a 250 Kilodalton Phosphodiesterase Interacting Protein (PDE4DIP), Shows a Novel Protein Interaction With Cardiac Myosin Binding Protein C
Authors: Farrell Emily T , Cai Wenxuan , De Lange Willem J , Ge Ying , Ralphe John C
Published: April 2022

Cardiac myosin binding protein C (cMyBP-C) is a sarcomeric protein important in the regulation of cardiac contraction through its phosphorylation-dependent interactions with myosin heavy chain and actin.
MYBPC3,
the gene encoding cMyBP-C, contains the largest number of hypertrophic cardiomyopathy (HCM)-causing mutations. Interestingly, the region of
MYBPC3
containing the greatest number of HCM-causing missense mutations, the central domains, have an unknown physiological relevance to the overall function of the protein. Intriguingly, central domain C3 contains a positively charged, putative surface binding interface for an as-yet unidentified ligand. Two of the most common HCM-causing mutations, R495Q and R502W, located in C3, appear to alter this charged interface. We have previously shown that these two mutations lead to altered contractile kinetics and hypophosphorylation of cMyBP-C. We hypothesize that this region of C3 contains an important binding region that is disrupted by both the R495Q and R502W mutations. To reveal candidate binding proteins, we performed a pull-down assay using mouse cardiac homogenate and a GST-tagged C2-C4 fragment of cMyBP-C, with or without the R495Q mutation. Mass spectrometry revealed that myomegalin, a 250 kDa phosphodiesterase-4D-interacting protein (PDE4DIP), bound the WT, but not the R495Q C2-C4 fragment. To confirm the interaction between cMyBP-C and myomegalin
in situ
, we performed Duolink proximity ligase assay (PLA) in cultured neonatal mouse cardiomyocytes which revealed a positive interaction in cMyBP-C
+/+
but not in cMyBP-C
-/-
cells (n>20) (Figure). Our data strongly suggest that a large isoform of myomegalin, separately known to form a protein complex with PKA/AKAP, forms a novel interaction with cMyBP-C. We hypothesize that perturbations in this interaction lead to altered PKA localization and the observed changes in R495Q and R502W cMyBP-C phosphorylation, and may contribute to the HCM phenotype.
Abstract 14015: Extracellular Vesicle-Associated microRNAs From the Plasma of HIV-Positive Individuals Enhance Atherosclerosis Burden
Authors: Da Fonseca Ferreira Andrea , Wei Jianqin , Zhang Lukun , Macon Conrad , Zhang Qianhuan , Jayaweera Dushyantha , Bellio Michael , Khan Aisha , Hare Joshua M , Dykxhoorn Derek , Wang Liyong , Dong Chunming
Published: April 2022

Introduction:
People living with HIV (PLHIV) have a higher risk of cardiovascular diseases (CVD) compared to HIV negative (HIV
-
) individuals. The molecular mechanisms underlying the increased CVD risk remain elusive. Extracellular vesicles (EVs) mediate cell-to-cell communication through cargo transfer, including microRNAs (EV-miRs).

Hypothesis:
HIV infection results in modification of plasma EVs cargo and these HIV positive EVs (HIV
posEVs
), specifically EV-miRs, recapitulate the effects of HIV infection on CVD development.

Methods:
Atherosclerosis burden was assessed by carotid ultrasound in 74 PLHIV treated with antiretroviral therapy (ART) with viral loads <50 c/ml and 23 HIV
-
subjects. Circulating endothelial progenitor cell (EPC) levels were measured by colony forming unit (CFU) assay. PLHIV plasma was fractionated into plasma EVs (HIV
posEVs
) and plasma-depleted of EVs (HIV
plasmadepEVs
). These

fractions, EVs from HIV
-
subjects (HIV
negEVs
) and PBS were injected weekly into apoE
-/-
mice via tail vein for three months. Atherosclerosis burden (H&E and Oil Red O staining), bone marrow (BM) EPC senescence (β-galactosidase staining), proliferation (MTT assay) and migration (“scratch” assay) were examined. RNASeq was used to identify EV-miRs that mediated the effects of HIV
posEVs
. Tailored EVs (TEVs) loaded with antagomirs for top EV-miRs were generated to determine their capacity to reverse the adverse effects of HIV
posEVs
in mouse EPCs
in vitro
.

Results:
PLHIV had higher atherosclerosis burden and lower circulating EPC numbers. Mice treated with HIV
posEVs
showed increased atherosclerotic burden, higher BM EPC senescence and lower functionality. HIV
posEVs
also negatively affected mouse BM EPC senescence
in vitro
. RNAseq identified four top candidate EV-miRs upregulated in HIV
posEVs
: let-7b-5p, miR-16-5p, miR-423-5p, and miR-103a-2. TEVs loaded with the antagomirs for let-7b and miR103a-2 counteracted the effects of HIV
posEVs
on the accelerated senescence of mouse BM EPCs.

Conclusion:
1) Plasma EVs from PLHIV reconstitute the effects of HIV infection on accelerated atherosclerosis via negatively affects EPC functionality; and 2) TEVs, targeting candidate EV-miRs counteracts the effects of HIV infection on EPCs.
Abstract 14018: lncRNA HAS2-AS1 Regulates Sunitinib-Induced Endothelial Dysfunction by Preserving the Endothelial Glycocalyx
Authors: Nukala Sarath Babu , Kwon Youjeong , Jousma Jordan , Yan Gege , Han Zhenbo , Cho Yoonje , Shao Ning-Yi , Lee Won Hee , Ong Sang-Ging
Published: April 2022

Introduction:
Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiotoxicities. Sunitinib, a multi receptor tyrosine kinase inhibitor, has been reported to cause vascular toxicity. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their role in cardio-oncology remains poorly understood.

Hypothesis:
We hypothesize that lncRNAs may be involved in sunitinib-induced endothelial dysfunction and may represent a target class amenable for therapeutic action.

Methods and Results:
We performed lncRNA expression profiling to identify potential lncRNA candidates that are dysregulated in human induced pluripotent stem cells-derived ECs (hiPSC-ECs) treated with sunitinib. We discovered sunitinib epigenetically repressed the expression of lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1). Downstream mechanistic studies revealed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced production of hyaluronic acid (HA) and aggrecan, two major constituents of the endothelial glycocalyx (EG), resulting in decreased viability, impaired angiogenesis, and increased vascular permeability. Supplementation of sunitinib-treated hiPSC-ECs with HA or overexpression of HAS2 restored the integrity of the glycocalyx and prevented sunitinib-induced endothelial dysfunction. These results were further validated in an in vivo mouse model of sunitinib-induced dysfunction as shown by reduced coronary flow reserve (CFR), degraded EG within the aorta, and increased vascular permeability.

Conclusions:
Our study established that deficiency of HAS2-AS1, coupled with reduced production of HA that is essential for proper glycocalyx formation, may be responsible for sunitinib-induced endothelial damage. Therapeutic strategies targeting the extracellular matrix components of the glycocalyx may represent a broad strategy to prevent sunitinib-induced endothelial dysfunction.
Abstract 14020: Right Ventricular Strain Predicts Adverse Outcomes in Patients Undergoing Coronary Artery Bypass Grafting
Authors: Duus Lisa S , Olsen Flemming J , Lindberg soeren , Fritz-Hansen Thomas , Pedersen Sune , Iversen Allan , galatius soeren , Mogelvang Rasmus , Biering-srensen Tor
Published: April 2022

Background:
Evolvement in speckle-tracking echocardiography (STE) enable a detailed layer-specific analysis of the right ventricular (RV), which has shown to be a promising way of quantifying RV systolic function. We aimed to evaluate the usefulness layer-specific RV free wall strain (RVFWS) for predicting cardiovascular outcome in patients undergoing coronary artery bypass grafting (CABG).

Methods:
We studied 317 patients scheduled for CABG, with echocardiography prior to surgery. RV STE was performed to acquire endocardial, midmyocardial, and epicardial RVFWS. The endpoint was a composite of heart failure (HF) or cardiovascular death (CVD). Cox proportional hazards regression were used to assess the prognostic value. The multivariable adjustments included among other age, sex, hypertension and LVEF. Restricted cubic spline models were created to visualize the incidence rate for each RVFWS.

Results:
Of 317 patients, 30 (9.5%) reached the endpoint at a median follow-up of 3.5 years. The mean age was 67 years, 83% were men, and the mean LVEF was 50%. In univariable analyses all three layers were associated with a higher risk of the outcome (figure). All three layers remained independently associated with the outcome after multivariable adjustment (endo: HR 1.07 (1.01-1.13), mid: HR 1.06 (1.01-1.12), epi: HR 1.06 (1.01-1.11), per 1% absolute decrease). Reduced endo-RVFWS and mid-RVFWS posed a two-fold increased risk of developing HF and/or CV death as compared to those with preserved RVFWS (incidence rate of 3.7 (2.39-5.63) vs. 1.5 (0.76-2.82), events per 100 patient-years for reduced and preserved endo-RVFWS as well as reduced and preserved mid-RVFWS). Patients with reduced epi-RVFWS did not exhibit a higher risk of the outcome as compared to those with preserved epi-RVFWS.

Conclusion:
In patients undergoing CABG, RVFWS is a predictor of cardiovascular outcomes, and particularly reduced endocardial and midmyocardial RVFWS pose an increased risk of outcome.
Abstract 14024: High-Field MRI Advanced Neuroimaging Characterization of Cerebrovascular Damage in a Mouse Model of Hypertension-Induced Cognitive Impairment
Authors: Carnevale Lorenzo , Carnevale Raimondo , Mastroiacovo Francesco , Perrotta Marialuisa , Carnevale Daniela , Lembo Giuseppe
Published: April 2022

Introduction:
Hypertension in one of the main risk factors for vascular cognitive impairment (VCI) and neurodegenerative pathologies as Alzheimer’s Disease (AD). To identify the underlying mechanisms it is important to use experimental models that present the pathophysiological characteristics of AD and VCI, hence allowing the investigation of molecular processes not explorable in humans. To ease the translational potential of these findings it is fundamental to characterize the brain damage with techniques easily applicable to the cognitive-declining patient, like MRI.

Methods:
Transverse aortic constriction (TAC) was performed in C57Bl/6J mice to induce severe hypertension to the cerebral vasculature and long term VCI. The cognitive performance at the Morris Water Maze (MWM) and Novel Object Recognition (NOR), the cerebrovascular injury by macro and microstructural MRI and cerebral blood flow (CBF) were analyzed. T2w volumetric images, diffusion tensor imaging, CBF sequences were performed on a small-animal dedicated 7 Tesla MRI.

Results:
TAC-hypertensive mice displayed significantly reduced learning capabilities, evidenced in the acquisition phase of MWM, and a marked impairment in spatial and short-term memory shown by probe trial in MWM and NOR test. At the structural MRI, TAC mice showed white matter microstructural degradation in the Fimbria, evidenced by a reduction of Fractional Anisotropy (SHAM vs TAC: 0.52±0.01 vs 0.44±0.02, p=0.047), coupled with a hypothalamic swelling (Right: SHAM vs TAC: 7.14±0.09 vs 7.50±0.11mm
3
, p=0.035; Left: SHAM vs TAC: 7.18±0.20 vs 7.91±0.17mm
3
, p=0.019). Hemodynamic alterations resulted in reduced cortical and hypothalamic CBF (Cortex: SHAM vs TAC: 96.6±3.4 vs 77.1±6.8 mL/100mg/min, p=0.046; Hypothalamus: SHAM vs TAC: 140±6 vs 122±4 mL/100mg/min, p=0.025). Furthermore the histological analysis evidenced a capillary rarefaction and reduced capillary-pericyte coverage in the prefrontal cortex, suggestive of a severe impact of the elevated blood pressure on the brain vasculature.

Conclusions:
In conclusion we have developed a mouse model of hypertension that reproduces typical tracts of the human pathology and a pipeline of analysis that will ease translate findings from bench to bedside.
Abstract 14027: National Trends and County-Level Patterns of Prescription for PCSK-9 Inhibitors Among Medicare Beneficiaries in the United States
Authors: Aghajani Nargesi Arash , Hanna Jonathan , Khera Rohan
Published: April 2022

Introduction:
PCSK9i are expensive but effective adjunctive lipid lowering therapies but their uptake in clinical practice has largely remained unknown.

Hypothesis:
We evaluated national trends and patterns of prescription for PCSK9i among Medicare beneficiaries.

Methods:
We identified lipid-lowering prescriptions in national Medicare Part D database for 2015-2018. To evaluate county level features associated with PCK9i prescriptions, data was merged with AHRQ sociodemographic measures, public health indices from County Health Ranking, and deprivation rank from Neighborhood Atlas. We evaluated trends and county level variation in proportionate PCK9i prescriptions relative to statins.

Results:
The number of PCSK9i prescribers increased from 16 in 2015 to 9621 in 2018, representing an increase from 0.01% to 3.0% of statin prescribers. There were 2980 counties with ≥10 statin prescribers in 2018, of which only 161 (5.3%) had any PCSK9i prescriptions. Even among counties with PCK9i use, relative to a median 8762 [IQR 7491-10767] for statin-receiving beneficiaries per 100k population, the rates of use were 6.1 [3.0-12.2] beneficiaries for PCSK9i and 177 [111-264] for ezetimibe. At a county level, proportionate PCSK9i beneficiaries relative to statin significantly correlated with county population (r=0.34), education (r=0.22), younger age (r=0.16), household income (r=0.14), lower prevalence of obesity (r=0.14), and lower deprivation rank (r=0.10). After accounting for sociodemographic and cardiometabolic risk factors in logistic regression, county population, education, lower median age, and lower prevalence of obesity significantly predicted PCK9i use.

Conclusion:
Despite an increased uptake of PCK9i during 2015-2018, only 3% of statin prescribers nationally use any PCSK9i among Medicare beneficiaries. The use is also restricted to only 5% of US counties, which were affluent, suggesting a need for an evaluation to ensure equitable use.
Abstract 14035: IL-4Ra-Mediated CD206
+
Macrophage Activation Promotes Adverse Remodeling in the Failing Heart
Authors: Wang Qiongxin , Ismahil Mohamed Ameen , Rokosh Gregg , Zhu Yujie , Hamid Tariq , Prabhu Sumanth
Published: April 2022

Background:
In heart failure (HF), cardiac macrophages are largely comprised of CD206
+
cells that locally self-renew independent of the blood monocyte pool. We tested the hypothesis that cardiac CD206
+
macrophages expressing interleukin (IL)-4Rα are key mediators of adverse left ventricular (LV) remodeling in HF.

Methods and Results:
Adult male C57BL/6 mice underwent non-reperfused myocardial infarction (MI) to induce HF. HF mice (vs. sham mice) exhibited progressive expansion of cardiac CD206
+
macrophages up to 8 w post-MI (accounting for ~80% total macrophages), whereas cardiac CD206
-
macrophages peaked at 48 h and then decreased by 90% at 1 w post-MI and beyond. Cardiac CD206
+
macrophage levels negatively correlated with LV ejection fraction, and positively correlated with remote zone fibrosis. These cells were predominantly CCR2
-
and nearly half expressed IL-4Rα, whereas CD206
-
macrophages, monocytes, neutrophils, and T-cells had markedly lower IL-4Rα expression. Bone marrow-derived macrophages (BMDMs) polarized with IL-4 (M[IL-4]) induced myofibroblast activation
in vitro
. Intramyocardial adoptive transfer of M[IL-4] macrophages (1 x 10
6
cells) into naïve mice induced progressive LV chamber dilation and dysfunction, and augmented cardiac fibrosis over 4 w. Next, sham and HF mice with similar LV remodeling at 4 w post-MI were given IL-4Rα-specific or control antisense oligonucleotides (ASOs) 40 mg/kg i.p. every 3 d for 4 w. HF mice receiving IL-4Rα ASOs exhibited profoundly diminished cardiac CD206
+
IL-4Rα
+
(and total CD206
+
) macrophage levels, substantially less macrophage proliferation and phagocytosis, and improvement of LV dysfunction, hypertrophy, and fibrosis. Moreover, both M[IL-4] CD206
+
BMDMs and CD206
+
IL-4Rα
+
macrophages in failing hearts expressed high levels of
Fizz1
(found in inflammatory zone 1). Blocking FIZZ1 expression and/or secretion blunted the profibrotic capacity of M[IL-4] CD206
+
BMDMs
in vitro
.

Conclusion:
CD206
+
IL-4Rα
+
macrophages proliferate and expand in the failing heart and are key drivers of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206
+
macrophage IL-4Rα signaling may be a fruitful therapeutic approach for alleviating LV remodeling in HF.
Abstract 14045: Increased Fibrosis and Microvessel Disease in Allograft Endomyocardial Biopsies of Children With Chronic Graft Failure Due to Cardiac Allograft Vasculopathy
Authors: Watanabe Kae , Arva Nicoleta , Arzu Jennifer , Robinson Joshua D , Rigsby Cynthia K , Markl Michael , Husain Nazia
Published: April 2022

Introduction:
The pathogenesis of chronic graft failure (CGF) in pediatric heart transplant recipients (PHT) is multifactorial and includes cardiac allograft vasculopathy (CAV). Prior research has shown that CGF can present as microvessel disease (MVD) and fibrosis on endomyocardial biopsies (EMB), however, optimal routine surveillance is not established. We analyzed EMB specimens to establish histopathologic findings of CGF represented by PHT with CAV.

Hypothesis:
PHT recipients with CGF secondary to CAV have increased fibrosis and MVD on EMB.

Method:
We performed a retrospective case-control study. PHT with moderate to severe (M-S) CAV diagnosed on cardiac catheterization between 2017-2020 were identified. EMB from time of M-S CAV diagnosis (CAV-EMB) was reviewed (excluding those with significant intercurrent rejection) and compared to their EMB prior to any CAV diagnosis (pre-CAV-EMB) and controls that were matched for age at and time since transplant (Tx) . Fibrosis was qualitatively graded on a scale of 0-5 and MVD was scored as number of capillaries with stenotic wall thickening (due to either endothelial cell swelling or medial hypertrophy) per fields of view.

Results:
Eight PHT with CAV-EMB and pre-CAV-EMB and 8 controls were identified. CAV-EMB group was 2.5 years (IQR: 0.9,8.0) old at time of Tx and 10.6 years post-Tx (8.3,15.5) at EMB. Pre-CAV-EMB was 1.8 years (1.1,2.8) prior to CAV-EMB. In the CAV, pre-CAV, and control groups median fibrosis score was 3.0 (2.0, 3.0) vs 2.0 (2.0, 3.0) vs 1.0 (0, 1.0) (p= 0.001) and MVD score was 2.1 (1.3, 2.9) vs 2.0 (1.6, 2.8) vs 0.5 (0.2, 0.7), respectively (p= 0.007). These were significantly different between pre-CAV-EMB vs controls (fibrosis p=0.003, MVD p=0.007) and CAV-EMB vs controls (fibrosis p=0.001, MVD p=0.005), but not between pre-CAV-EMB vs CAV-EMB. Furthermore, fibrosis and MVD scores were strongly correlated (r=0.78, p<0.001).

Conclusion:
Histopathological evidence of increased fibrosis and MVD is noted in EMB with CGF secondary to CAV and these findings pre-date angiographic CAV diagnosis. Further studies in larger PHT cohorts are needed to assess time course of fibrosis and MVD to improve surveillance of CAV and CGF.
Abstract 14052: Outcomes of Radiofrequency Transcatheter Ablation of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy. A Systematic Review and Meta-Analysis
Authors: Latif Azka , Ahsan Muhammad J , Jaffri Abbis , Willman Claire C , kapoor vikas , Mirza Mohsin , Kim Michael H
Published: April 2022

Introduction:
Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM). Radiofrequency transcatheter ablation (RFCA) for AF in patients with HCM is beneficial, however, its efficacy and safety is not well characterized. This meta-analysis aimed to access the efficacy of RFCA in patients with HCM and concomitant AF.

Methods:
PubMed, Embase, Cochrane, ClinicalTrials.gov, and Google Scholar were searched for studies evaluating the efficacy of RFCA for AF in patients with HCM from January 1, 2000, until April 2021. The outcomes data regarding the efficacy of RFCA after a single or multiple procedures was assessed. The analysis was performed using a random-effects-model using the Mantel-Haenszel method and results presented as 95% confidence interval using STATA version 15.1 software.

Results:
Sixteen observational (N=769) studies were included. The mean time after the first procedure was ≥12 months and the meantime after multiple procedures was 3 years. The mean age was 57.5+/-8.3 years and 30% of patients were women. Single-procedure freedom

from AF at the latest follow-up was 38.67% (95% CI: 33.38-44.10%, I2 =54.55%) reported by 15/16 studies (Fig 1A). With multiple procedures, the final success rate was 45.648% (95% CI: 37.52-53.90, I2=75.9%) reported by 15/16 studies (Fig 1B)

Conclusions:
RFCA of AF in patients with HCM appears to be safe and feasible, although these patients have lower overall success rates compared to a more typical AF ablation population. HCM patients also require multiple procedures to gain intermediate success rates.
Abstract 14055: Increased Coronary Myogenic Tone in Patients With Poorly Controlled Hypertension
Authors: Feng Jun , Liu Yuhong , Phillips Ronald , Del Re Andrew , Ehsan Afshin , Kononov Martin , Sodha Neel , Sellke Frank W
Published: April 2022

Background:
Both animal and clinical studies have demonstrated that hypertension is associated with altered vasomotor tone. However, the direct effect of well-controlled and poorly (un)controlled hypertension on the myogenic tone of human coronary arterioles is inadequately investigated.

Objective:
We investigated the effect of well-controlled and poorly (un)controlled HTN on the myogenic tone of human coronary arterioles.

Methods:
Coronary arterioles pre-cardiopulmonary bypass were dissected from harvested atrial tissue samples of eligible patients. Patients were categorized as having normal blood pressure, or well-controlled or poorly-(un)controlled hypertension (n = 5-8/group). Myogenic tone in response to stepwise increases in intraluminal pressure was studied between pressure steps. The microvascular reactivity in response to the selective α-adrenergic agonist phenylephrine was also assessed via vessel myography.

Results:
Increased myogenic tone was reflected by a decreases in microvessel internal diameter in all patients. There was a significant increase in myogenic tone in patients with poorly (un)controlled hypertension (0.97±0.05 in diameter ) compared with normotensive patients (1.27±0.14 in diameter, P = 0.001). The contractile response to phenylephrine was significantly enhanced in patients with poorly (un)controlled hypertension compared with normotensive patients (P<0.001). However, there were no significant differences in the myogenic tone or phenylephrine-induced vasomotor tone between normotensive patients and patients with well-controlled hypertension (P>0.05 respectively).

Conclusion:
Poorly (un)controlled hypertension is associated with increases in coronary arteriolar myogenic and vasomotor tone, which may contribute to the increased coronary vasospasm seen in this population.
Abstract 14085: Evaluating the Geographical Dispersion and Outcomes of Carotid Artery Revascularization in the United States: A Report From the Vascular Quality Initiative
Authors: Young Michael N , Henkin Stanislav , Kearing Stephen , Iribarne Alexander , Goodney Philip P , Columbo Jesse
Published: April 2022

Introduction:
Carotid artery revascularization - including endarterectomy (CEA) and stenting (CAS) - is the standard of care for severe carotid stenosis. The contemporary geographic dispersion of CAS relative to CEA is not well described and has implications on access-to-care in the United States.

Methods:
We identified 83,825 patients undergoing CEA and CAS between 2015-2019 among participating centers in the Vascular Quality Initiative. Patients were stratified according to type of revascularization and by urban vs. rural geographical designation based on Rural Urban Commuting Area coding. For CEA and CAS cohorts, demographic profiles and clinical outcomes were compared between urban vs. rural patients. Multivariable logistic regression was performed to estimate the association of geographical locale with 30-day and 1-year outcomes.

Results:
There was a progressive annual increase in CAS, CEA, and the relative ratio of CAS/CEA performed throughout the study period. (Figure 1) The proportion of carotid stents increased from 25.1% in 2015 to 48.7% in 2019. This finding was consistent in both rural (28.7% to 51.4%) and urban areas (23.9% to 47.7%). In both CEA and CAS cohorts, demographic characteristics, medical profiles, and in-hospital outcomes were overall comparable between rural and urban subgroups. For CAS, geographic locale was not associated with 30-day or 1-year mortality (OR 1.12, 95% CI 0.89-1.41; p=0.34 and OR 1.11, 95% CI 0.97-1.28; p=0.13, respectively). Similarly for CEA, 30-day and 1-year mortality were not significantly different between rural vs. urban subgroups (OR 1.04, 95% CI 0.84-1.29; p=0.72 and OR 1.05, 95% CI 0.94-1.17; p=0.40).

Conclusions:
Over a short time period, there has been progressive uptake in the relative use of CAS and CEA across the United States. There were no significant differences in either short- or long-term outcomes of carotid revascularization based on rurality.
Abstract 14088: Ventricular Longitudinal Function by CMR Predicts Heart Failure Associated Morbidity in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Berg Jonathan , Åkesson Julius , Jablonowski Robert , Solem Kristian , Heiberg Einar , Borgquist Rasmus , Arheden Håkan , Carlsson Marcus
Published: April 2022

Ventricular longitudinal function measured as basal-apical atrioventricular plane displacement (AVPD) or global longitudinal strain (GLS) are potent predictors of mortality and could potentially be predictors of morbidity in heart failure (HF). We hypothesize that decreased AVPD and GLS are associated with increased morbidity measured. Patients with HFrEF (EF≤40%) referred to a CMR exam were considered for inclusion. Ventricular longitudinal function, ventricular volumes and myocardial fibrosis or infarctions were analyzed. National registries provided data on cause of cardiovascular hospitalizations and cardiovascular mortality and this was used as a composite endpoint. A time-to-event analysis capable of including reoccurring events were employed with 5-year follow-up. HFrEF patients (n=287, age 62±12, 78% male) had EF 26.5% (SEM 0.5), AVPD 7.8 mm (SEM 0.1) and GLS -7.5% (SEM 0.2). There were 578 events in total and the vast majority was HF hospitalizations (n=418). Other major events were revascularizations (n=64), cardiovascular deaths (n=40) and myocardial infarctions (n=21), and 155 (54%) patients experienced at least one event (Mean 2.0, range 0-64). Patients in the bottom AVPD or GLS tertile (<6.8mm or >-6.1%) experienced over 3 times as many events compared to the top tertile (>8.8 mm or <-8.4%, p<0.001) (Figure 1). In multivariate analysis adjusted for significant variables, AVPD and GLS remained as independent predictors of events (HR 1.12 per-mm-decrease and HR 1.13 per-%-increase) (Table 1). In conclusion, ventricular longitudinal function, measured either as AVPD or GLS, have independently prognostic implications for morbidity in HFrEF patients.