bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17018: Amputation After Atherectomy: Studying Long-Term Outcomes Using an Instrumental Variable Method
Authors: Ramkumar Niveditta , Columbo Jesse A , Camblor Pablo M , O’Malley A. James , Goodney Philip P
Published: July 2021

Introduction:
Outcomes for atherectomy remain poorly characterized. Our objective was to use instrumental variable (IV) analysis to compare long-term amputation rates in patients receiving atherectomy versus other traditional peripheral vascular interventions (PVI) approaches.

Methods:
We queried the Medicare-linked Vascular Quality Initiative registry for patients undergoing PVI from 2010-2015. The exposure was treatment: atherectomy (+/- balloon angioplasty) versus other PVI types. The primary outcome was amputation. We used the proportion of atherectomy procedures of all PVIs performed at each hospital as an IV and compared the estimates from IV analysis to multivariable Cox regression and propensity-matched estimates.

Results:
In this cohort of 19693 patients, 2103 (10%) received atherectomy. Compared to patients receiving other PVI, patients receiving atherectomy were more likely to have a femoropopliteal artery (65% vs 48%, p<0.001) treated with worse disease severity (TASC B and greater: 77% vs 69%, p<0.001). The 5-year overall amputation rate was 31% (158 amputations per 1000 patients/year) in patients receiving atherectomy versus 24% (105 amputations per 1000 patients/year) for other PVIs (log-rank p<0.001). Without adjustment, patients undergoing atherectomy were 40% more likely to have an amputation (Figure 1). After adjusting for patient demographics, comorbidities, and disease characteristics, this effect was mitigated to 15% and 16% for multivariable Cox and propensity-matched approaches, respectively. However, after the IV adjusted analysis accounted for unmeasured confounders, patients receiving atherectomy versus non-atherectomy PVI were 78% more likely to have an amputation.

Conclusions:
Patients receiving atherectomy were more likely to have an amputation. Unmeasured confounders such as selection bias may play an important role in the long-term risk of amputation for patients undergoing atherectomy.
Abstract 17054: Sex-Related Differences in Atherosclerosis Burden and Composition Evaluated by Magnetic Resonance: A Complex Interaction Between Visceral Adiposity and Atherogenic Lipoproteins
Authors: LeBlanc Stéphanie , Coulombe François , Bibeau Karine , Bertrand Olivier F , Pibarot Philippe , Després Jean-Pierre , Larose Eric
Published: July 2021

Introduction:
Visceral adiposity increases the level of atherogenic lipoproteins and is linked to sex-related differences in cardiovascular risk.
Hypothesis.
Atherogenic lipoproteins could mediate the relationship between visceral fat and sex-related differences in atherosclerosis burden and composition, including the lipid-rich necrotic core (LRNC).

Methods:
This study included 294 women (39.4 ± 15.0 years) and 324 men (39.5 ± 13.8 years), matched for age and risk factors (hypertension, dyslipidemia, obesity, diabetes, smoking). Carotid atherosclerosis, visceral abdominal fat (VAT) and cardiac fat (CAT) were studied by magnetic resonance imaging.

Results:
For similar age and risk profile, women had less VAT (
p
<0.001) and CAT (
p
<0.001) than men. Carotid atherosclerosis prevalence (
p
<0.001) and carotid wall volume (
p
<0.001) were higher in men. Although LRNC prevalence was similar in women and men (
p
=0.23), men had a greater LRNC volume (
p
<0.001). An interaction was observed between waist-to-hip ratio (WHR) and sex on LRNC volume (
p
=0.025). There was also an interaction between sex, VAT, and total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C) on LRNC volume (
p
=0.012), beyond age and risk factors (
p
=0.011). Only 8.6% of men and none of the women were classified at high risk (presence of LRNC) by the Framingham Risk Score while 35.4% of men and 14.0% of women were classified at high risk by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) risk score (risk of advanced atherosclerosis). Elevated TC/HDL-C (≥3) and/or WHR (≥0.8 in women, ≥0.9 in men) were superior to the PDAY risk score, identifying 62.2% of women (Net Reclassification Improvement [NRI]=1.85,
p
<0.001) and 79.3% of men (NRI=0.26,
p
<0.001) with LRNC.

Conclusions:
Women had less visceral adiposity, carotid atherosclerosis burden and LRNC volume, independently of age and risk profile. Carotid LRNC volume varied with sex, VAT, and atherogenic lipoproteins. WHR and TC/HDL-C improved the identification of high-risk carotid atherosclerosis features in women as well as men. This evidence supports the clinical potential of the atherogenic lipoprotein profile and of adiposity distribution in atherosclerosis risk evaluation of both women and men.
Abstract 17064: Enrichment of Cardiotoxic Gene Expression Profile in Human Induced Pluripotent Stem-Cell Derived Cardiomyocytes in Response to Tyrosine Kinase Inhibitor Nilotinib
Authors: Aggarwal Praful , White Matthew , Matter Andrea , Turner Amy , Olson Benjamin , Broeckel Ulrich
Published: July 2021

Small molecule tyrosine kinase inhibitors (TKIs) are a valuable class of therapeutics with widespread clinical utility against multiple cancers. However, there is strong evidence that TKIs are associated with cardiotoxicity and adverse cardiovascular events. Our understanding of the underlying mechanisms related to TKI induced cardiotoxicity is limited. Human iPSC derived cardiomyocytes (hiPSC-CMs) provide a flexible platform and unique model to study the underlying molecular mechanisms associated with TKI associated cardiotoxicity. In this study we describe the gene expression profile between hiPSC-CM cell lines which exhibit susceptibility vs. resistance. RNA-seq analysis was performed in hiPSC-CM cell lines from six participants in the NHLBI HyperGEN study (A to F). Experiments were performed in triplicate using sunitinib (SUN), vandetanib (VAN), gefitinib (GEF) and nilotinib (NIL). We analyzed beat rate, cell index and ATP viability as physiological measurements of CM toxicity and defined a 20% change from the normalized control as TKI susceptibility. Differential gene expression analysis was performed using DESeq2. We observed significant physiological differences between the different hiPSC-CMs after TKI treatment (beat rate, cell index and ATP viability). The most variable cell index and beat rate response was observed for NIL. Based on cell index, lines B, D, E were resistant while A, C, F were significantly more susceptible to NIL. Principal component analysis showed that the variance in gene expression was the highest after NIL treatment when compared to controls (16% for NIL; 11% for VAN; 6% for SUN and 5% for GEF). A total of 567 genes exhibited significant differential expression changes (adj. p-value ≤ 0.1) after NIL treatment in susceptible versus resistant lines. Pathway analysis showed significant enrichment for cardiotoxicity including pathways implicated in cardiac infarction, fibrosis, hypertrophy, and congestive cardiac failure. Taken together, our results identify unique gene expression changes associated with TKI cardiotoxicity. Furthermore, the variability in TKI susceptibility between different hiPSC-CM lines highlights the need to comprehensively assess cardiotoxicity in a diverse set of lines on a physiological and molecular level.
Abstract 17067: MAVERICK-HCM: Phase 2 Randomized, Multi-Center, Double-Blind, Placebo-Controlled Concentration-Guided Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy
Authors: Heitner Stephen , Wang Andrew , Jacoby Daniel , Lester Steven , Carlson Timothy , Zhang David , Sehnert Amy , Ho Carolyn
Published: July 2021

Introduction:
Hypertrophic cardiomyopathy (HCM) carries substantial lifelong morbidity. Mutations in sarcomeric proteins that lead to HCM cause excess contractility, poor relaxation, and inefficient energy utilization. Although obstructive physiology is a prominent feature of disease, approximately 30% of HCM patients experience symptoms in the context of non-obstructive HCM (nHCM). Management options are extremely limited with little other than cardiac transplantation to offer severely affected patients. Mavacamten (MAVA), a first-in-class small molecule, is a selective modulator of cardiac myosin that inhibits the cardiac myosin ATPase to reversibly attenuate cardiac contractility. In addition to its effects on contractility, MAVA has been shown to improve LV compliance in preclinical and clinical studies. The Phase 2 MAVERICK-HCM study is designed to evaluate safety and tolerability, and to provide pilot data on the effects of MAVA on biomarkers, cardiac function, and exercise capacity in nHCM.

Methods:
This double-blind study will enroll 60 individuals with nHCM (Left ventricular outflow tract gradient <30 mmHg; resting or provoked), NYHA Class II or III, and LVEF ≥55%. Subjects will be randomized 1:1:1 to one of two target plasma drug concentrations (Group 1: ~200 ng/mL and Group 2: ~500 ng/mL) or placebo for 16 weeks. The starting dose of MAVA is 5 mg, with one-step dose titration at Week 6 based on plasma drug concentration. Predefined criteria, including LVEF, will guide study drug discontinuation if indicated. Cardiopulmonary exercise testing will be performed at baseline and Week 16 to assess the impact on exercise capacity. The primary endpoint is the frequency and severity of treatment-emergent adverse events. The study design also includes multiple secondary endpoints including echocardiographic measures of diastolic function, NT-proBNP levels, patient reported outcomes, and physical activity by wearable accelerometer. An independent data monitoring committee will oversee safety.

Conclusions:
MAVERICK-HCM is testing a novel therapy to improve symptom burden in nHCM; a patient cohort currently lacking effective treatment. By targeting a core molecular mechanism of disease, MAVA has the potential to alter natural history.
Abstract 17070: Bmpr1a and Its Role in Endomt in Pulmonary Arterial Hypertension
Authors: Lee Heon-Woo , Adachi Takaomi , Park Saejeong , Kowalski Piotr , Anderson Daniel , Simons Michael , Jin Suk won , Chun Hyung J
Published: July 2021

There is emerging evidence that the aberrant pulmonary vascular remodeling that occurs in pulmonary arterial hypertension (PAH) is at least in part driven by the transformation of endothelial cells to mesenchymal cells (EndoMT), but the mechanism driving this pathobiology remains to be fully elucidated. Bone morphogenetic protein (BMP) signaling has been implicated to be involved in EndoMT in different vascular contexts, but the exact mechanism in the pulmonary vasculature remains to be defined. We describe the role of BMP receptor type 1A (BMPR1A or ALK3) as a key factor for maintenance of endothelial fate and suppression of EndoMT in the pulmonary vasculature. We found that inducible endothelial specific deletion of
Bmpr1a
in mice (

Bmpr1a
iECKO

) resulted in spontaneous EndoMT, with significant increase in smooth muscle actin (SMA) positive cells, associated with extensive pulmonary vascular remodeling and fibrosis.

Bmpr1a
iECKO

mice developed spontaneous pulmonary hypertension (PH) that was mediated by augmented TGF-β signaling driven by increased TGFBR2 expression, resulting in aberrant SMAD2/3 activation. Increased TGFBR2 expression in BMPR1A deficient state was secondary to increased activity of the transcription factor TCF3, whose negative inhibition by ID2 is abrogated in BMPR1A deficient state. EndoMT and PH secondary to loss of endothelial BMPR1A was effectively rescued by concurrent knockdown of TGFBR2. Overall, these studies define a mechanism of EndoMT driven by loss of endothelial BMPR1A, and demonstrate the efficacy of inhibiting EndoMT as a potential novel therapeutic strategy in PAH and other EndoMT-related vascular disorders.
Abstract 17080: A 3D Printed Ex Vivo Left Heart Simulator Quantifies and Validates Posterior Ventricular Anchoring Neochordoplasty
Authors: Paulsen Michael J , Bae Jung Hwa , Imbrie-Moore Annabel M , Wang Hanjay , Farry Justin M , Lin Michael A , Hironaka Camille E , Lucian Haley J , Edwards Bryan B , Thankore Akshara D , MacArthur John W , Steele Amanda N , Stapleton Lyndsay , Williams Kiah M , Deschamps Daniela , Kulkarni Rohun , Cutkosky Mark R , Woo Y. Joseph
Published: July 2021

Introduction:
The posterior ventricular anchoring neochordal (PVAN) repair is a nonresectional, single-suture technique for correcting posterior leaflet prolapse. While this technique has demonstrated clinical efficacy, a possible limitation is the stability of the suture anchored into myocardium as opposed to the fibrous portion of a papillary muscle.

Hypothesis:
We hypothesize that the PVAN suture serves only to position the leaflet for coaptation, after which systolic forces will be distributed throughout the valve, resulting in low peak forces on the suture.

Methods:
A left heart simulator was constructed using 3D printing, tuned to generate physiological pressure and flow waveforms, then validated. Porcine mitral valves (n=9) were dissected and mounted within the simulator. Chordal forces were measured using Fiber Bragg Grating (FBG) sensors, sewn in place using PTFE suture. FBG sensors are strain gauges made of 125
μ
m optical fibers that use reflected peak wavelength changes to measure strain. Hemodynamic and echocardiographic data were also collected. Isolated severe mitral regurgitation (MR) was induced by cutting P2 primary chordae. The valve was repaired using the PVAN technique, anchoring the suture to a customized force-sensing post positioned to mimic
in vivo
placement.

Results:
Forces on 1° and 2° chordae of both anterior and posterior leaflets were significantly elevated in the prolapse condition (
P
< 0.05). PVAN resulted in elimination of MR in all valves, as well as normalization of chordae forces to baseline levels for posterior primary (
P <
0.01
)
, posterior secondary (
P <
0.01
)
, and anterior primary chordae (
P <
0.05
)
, with reduction in anterior secondary chordal forces approaching significance (
P
= 0.055
)
. Peak forces on the PVAN stitch were minimal, even compared to the forces experienced by primary chordae of normal, healthy valves (
P
< 0.05).

Conclusions:
The PVAN technique eliminates MR by effectively positioning the posterior leaflet for optimal coaptation, distributing the forces amongst the subvalvular apparatus. Given the extremely low forces involved, the strength of the ventricular anchoring suture and myocardial anchoring point should not be a limiting factor.
Abstract 17116: Packed Red Cell Age Associated With Adverse Cardiovascular Changes in an Ovine Model of Septic Shock Resuscitation
Authors: Fanning Jonathon P , Obonyo Nchafatso G , Tung John-Paul , Byrne Liam , Simonova Gabriela , Diab Sara , Dunster Kimble , Passmore Margaret , Boon Ai-Ching , See Hoe Louise , Engkilde-Pedersen Sanne , Esguerra-Lallen Arlanna , Hashairi Fauzi Mohd , Pretti Pimenta Leticia , Millar Jonathan , Anstey Christopher , van Haren Frank , Cullen Louise , Suen Jacky , Shekar Kiran , Maitland Kathryn , Fraser John
Published: July 2021

Introduction:
Packed red blood cell (PRBC) transfusion in septic shock is generally reserved as a last resort hemodynamic resuscitative measure or for haemoglobin less than 7.0 g/dL.
Ex-vivo
preservation and storage predispose PRBCs to biochemical / mechanical changes whose impact in a septic host is unknown. This randomised pre-clinical trial specifically evaluates select markers of cardiovascular stress in an ovine model of endotoxemic shock receiving either fresh or stored blood.

Methods:
Twenty six anesthetised and mechanically ventilated merino ewes were randomly divided into endotoxemic shock (n = 16) or healthy (n = 10) groups. Endotoxemic shock was induced over 4 hours by infusing an escalating dose (total 11.25 mcg / kg) of lipopolysaccharide, LPS (
E.coli 055:B5
). During the last hour of LPS infusion, 10 mls / kg of either fresh, ≤ 5 days (n = 8) or stored, ≥ 30 days (n = 8) ovine packed PRBCs were administered. Healthy ewes received either fresh, ≤ 5 days (n = 5) or stored, ≥ 30 days (n = 5) ovine PRBCs at corresponding time points. Invasive haemodynamic monitoring and serial echocardiographic assessments were performed in all. Blood samples were measured for cardiac troponin I (cTnI), atrial natriuretic peptide (ANP) and hyaluronan at baseline (T0), 1, 3, 4, 5, 10 and 16h after which the ewes were euthanized.

Results:
Stored versus fresh PRBCs produced raised hyaluronan levels (P < 0.001) from T3 onwards in both sepsis and healthy groups and resulted in significant (P < 0.001) adverse haemodynamic changes (cardiac index, central venous pressure, pulmonary artery pressure and mixed venous oxygen saturation). Elevated ANP was observed between T3 to T10 (P < 0.001) in septic compared to healthy ewes but there was no association with age of PRBCs. No statistical differences were observed between groups for TnI.

Conclusions:
Sepsis and storage duration of PRBCs are associated with increased cardiovascular stress suggesting that stored PRBCs may predispose patients with septic shock to poor clinical outcomes.
Abstract 17120: Metabolic Syndrome Induces Long Lasting Phenotype in Bone Marrow-Derived Macrophages and Their Progenitor Cells Through Oxidative Stress and Histone H3-Lysine 4 Methylation State
Authors: Thiruppathi Muthusamy , Barman Pijus , Fang Milie , Fantuzzi Giamila , Benevolenskaya Elizabetta , Koh Timothy , Urao Norifumi
Published: July 2021

Metabolic syndrome is associated with low-grade inflammation and accumulation of inflammatory macrophages with largely unknown mechanisms. Here we report that bone marrow-derived macrophages (BMM) and their progenitor cells develop long lasting pro-inflammatory phenotype in metabolic syndrome. Using mice fed a high-fat diet (HFD) or a normal diet (ND), we found that BMM generated from HFD mice (BMM-HFD) exhibit higher transcription activities of pro-inflammatory genes than BMM generated from ND mice (BMM-ND). This is associated with increased oxidative stress (2.7-fold) and histone H3-lysine 4 tri-methylation (H3K4me3)( %), along with increased Set7 H3K4 methyltransferase (41%), in BMM-HFD. KDM5A H3K4 demethylase, however, is not changed in its levels but in its subcellular localization—increased extranuclear localization—in BMM-HFD. In addition, lower nuclear KDM5 enzymic activity was found in their BM progenitor cells (40%), and it was reversed by reduction of oxidative stress, resulting in reduction in H3K4me3 levels in those cells (33%). ChIP-PCR analysis revealed that H3K4me3 is increased at promoter lesions of potential KDM5A-targeted genes such as
Tnf
,
Il6
and
Cdkn2a
. Moreover, adoptive transfer experiment in hindlimb ischemia, BM progenitor cells from HFD mice induce accumulation of pro-inflammatory macrophages, establishing a link between BM progenitor cells and macrophages in vivo. In summary, our result suggest that metabolic syndrome induces oxidative stress at the BM progenitor level, which causes long lasting inflammatory phenotype of their derived macrophages in vitro and in vivo. This causal effect may be mediated by oxidative stress and enzymes regulating H3K4me3.
Abstract 17123: Hierarchical Clustering in 2014 Medical Expenditure Panel Survey (MEPS) to Examine the Cost of Events Related to Acute Myocardial Infraction (AMI) and Hypertension (HTN)
Authors: Saxena Anshul , Veledar Emir
Published: July 2021

Introduction:
Every year more than 75 million adults are diagnosed with HTN in the US. Despite spending $50 billion/ year to lower mortality related to HTN, only about 54% of patients have this condition managed. In 2014, mortality due to HTN or related complications was 410,000. AMI is a more severe manifestation of coronary artery disease with 735,000 people diagnosed yearly. It is estimated that hospitals lose $4493-$7940 per patient due to AMI. We studied costs for events associated with HTN and AMI in MEPS.

Methods:
Individuals aged ≥20 in MEPS (2014) were included. Hierarchical clustering was used for analysis. Age, sex, education status, race, Hispanic ethnicity, US citizenship status, family income, insurance, people who reported HTN and/ or AMI events were entered as dimensions. Cluster and descriptive analyses were adjusted for survey weights.

Results:
About 236 million weighted individuals were eligible for the analysis (Female: 51.7%; White: 79.1%; High school or above: 61%; Any private insurance: 66%; and Income≥ 400% of poverty line: 41%). Out of these, about 4.9 million participants reported costs/ events related to AMI and 61.8 million related to HTN. Five groups were identified based on similarity within each cluster (Table 1). The maximum number of participants were present in cluster 1 (weighted
n
= 101 million) with the most number of participants (21.5%) who reported HTN among all cluster groups. In general, cluster 5 had the lowest annual total of direct health care payments and events. Selected medical history is described in Table 2.

Conclusion:
Results show insights into the cost of HTN and AMI events, and their relationship with other comorbid conditions. Being computationally demanding, clustering methodologies are rarely utilized in survey data analysis. This could be the first example of clustering approach applied to data from MEPS. Once clustering methods are improved in weighted survey data, estimates will be more reliable.
Abstract 17139: Incidence and Outcomes of Infectious Endocarditis Six Months After Transcatheter Aortic Valve Implantation
Authors: Kuttamperoor Francis , Yandrapalli Srikanth , Atti Varunsiri , Siddamsetti Sisir , Frishman William
Published: July 2021

Background:
Infectious endocarditis (IE) is a known complication after transcatheter aortic valve implantation (TAVI). Available data suggest that IE was infrequent after TAVI but was associated with substantial mortality. We sought to determine the 6-month incident rates and outcomes of this complication after TAVI in the United States representative patient population.

Methods:
A weighted sample of adult patients who underwent TAVI and survived to discharge were identified in the Nationwide Readmissions Database January to June 2014 using appropriate ICD-9 codes. Among these patients, readmissions within 180-days in which IE was diagnosed were identified. Microbiology, complications, valvular procedural utilization, and mortality with IE were the outcomes studied.

Results:
Of 7,834 patients (mean age 81 years, 52% men) who underwent TAVI during the study period, 61 patients (0.8%; mean age 79 years, 58% men) had IE within 180 days form discharge. Median day to developing IE was 79 days [interquartile range 49-124 days]. Septicemia was present in 43 patients (71%) of which 15 (24%) developed septic shock. Gram positive bacteremia was frequent with 13 patients (21%) having
Streptococcal
bacteremia, and 12 (19%) with
Staphylococcal
bacteremia. Gram negative organisms were identified in 4%. Heart failure developed in 46 patients (75%), respiratory failure in 12 (20%), and acute kidney injury in 18 (29%). Concomitant pneumonia was present in 8 patients (13%). A valvular intervention was not performed in any of the 61 patients and 13 patients (22%) died in-hospital after IE diagnosis.

Conclusions:
Nearly 8 out of every 1000 patients undergoing TAVI developed IE within 6 months post-procedure. IE post TAVI was most commonly caused by gram positive bacteria and was associated with very high rates of multi-system complication. A valvular intervention was not performed in these sick patients with IE, and 1 out of 5 patient who developed IE died.
Abstract 17162: Ambient Ultra Fine Particle Exposure Impairs Gut Vascular Barrier via Notch Signaling
Authors: Chang Chih-Chiang , Baek Kyung In , Ding Yichen , Sioutas Constantinos , Li Rongsong , Hsiai Tzung
Published: July 2021

Introduction:
Ultrafine particles (UFP,
d
< 0.1 μm), a major sub-fraction of particulate matter (PM
2.5
,

d
< 2.5μm) in air pollutant, have been reported to increase cardiovascular morbidity. UFP promote endothelial dysfunction/permeability associated with Notch inhibition and degradation of tight junction protein. Gut vascular barrier (GVB) is a distinct protective barrier that inhibits translocations of antigens across the gut lumen, preventing infections by oral digestions. Here, we hypothesized UFP impair GVB by attenuating Notch signaling and disrupting tight junction protein.

Method:
The transgenic Tg(
flk1:mCherry
) zebrafish embryos were immobilized in neutralized tricaine solution and mounted in 2% low melting agarose to perform micro-gavage at 5 days post fertilizations (5dpf). A mA mixture of 10 kD FITC conjugated dextran and phenol red dye wasere micro-gavaged on the intestinal bulb with or without UFP at 25 μg/mL. Anterior trunk and posterior cardinal vein (PCV) post micro-gavage were imaged under a confocal microscope. Notch signaling related genes including the Notch ligand, Dll4, and the target, HES1, and the level of tight junction protein genes zonula occludens-1 (ZO-1) and Occludin (OCLN) mRNA expression following different courses of exposure to UFP were assessed in Human Aortic Endothelial Cells (HAEC) with quantitative RT-PCR.,

Result:
In the control group, the majority of FITC-dextran remained inside the gastrointestinal system. On the other hand, UFP exposure developed a significant accumulation of FITC-dextran in the intersomatic spaces (ISS) between the dorsal aorta (DA) and the PCV. This finding supports evidence of UFP exposure disrupted both the epithelial boundary and the endothelial vascular layer of the gut. In addition, Notch signaling related gene (HES1, DLL4) and the tight junction proteins genes (ZO-1, OCLN) expressions in HAEC were downregulated in concentration and time-course dependent manner by the exposure to UFP.

Conclusion:
The UFP exposure affected GVB homeostasis and increased endothelial permeability. This finding supports the link between ambient air pollutant exposure to the impairment in the gastrointestinal system.
Abstract 17170: Sarcomere Gene Mutation Hypertrophic Cardiomyopathy Exhibits Distinct Age-Dependent Adverse Remodeling
Authors: Kabani Samat , Concannon Maryann , Saberi Sara , Day Sharlene , Helms Adam S
Published: July 2021

Introduction:
Hypertrophic cardiomyopathy (HCM) due to mutations in sarcomere genes (G+HCM) has been associated with greater risk of adverse outcomes compared to genetic-test negative HCM (G-HCM). HCM morphologic progression across the age spectrum has not been well-defined in the presence or absence of sarcomere mutations.

Hypothesis:
We hypothesized that G+ HCM is associated with greater adverse remodeling than G- HCM across the age spectrum of adult HCM.

Methods:
In a prospectively collected HCM cohort, we studied adult HCM probands who had preserved systolic function (EF >50%). To ascertain morphologic differences with age, we compared the continuous variables of left atrial size/body surface area (LA/BSA) and maximum wall thickness (MWT) by echocardiogram, analyzed by age subgroup and by linear regression.

Results:
Of 500 HCM probands, 241 were G+ and 259 were G-. MWT was larger for all G+ compared to all G- (19.2mm +/- 6.4mm vs. 16.8mm +/- 4.7mm, p<0.001). By age subgroup, MWT was larger for G+ for ages 20-40 (20.1mm vs 15.7mm, p<0.001) and ages 40-60 (19.4mm vs 16.3mm, p<0.001) but not different for 60+ (17.8mm vs 18.1mm, p=0.8). In linear regression by age, there was no significant change in extent of MWT with age among G+ (p=0.7). In contrast, G- patients exhibited a positive correlation of greater MWT with age (p<0.001), which was significantly different than the age relationship for G+ (p=0.008). LA/BSA was larger for all G+ compared to all G- (21.9mm/m
2
+/- 3.9mm/m
2
versus 20.9mm/m
2
+/- 3.8mm/m
2
, p<0.006). By age subgroup, LA/BSA was not significantly different for G+ compared to G- ages 20-40 (20.9mm/m
2
vs 19.9mm/m
2
, p=0.193) but significantly larger for ages 40-60 (21.6mm/m
2
vs 20.0mm/m
2
, p<0.01) and age 60+ (24.5mm/m
2
vs 22.6mm/m
2
, p=0.02). The regression slopes were similar for G+ vs G- (0.07 mm/m
2
/yr versus 0.09mm/m
2
/yr, p=0.36) but the elevations were significantly larger for G+ (p<0.0001), indicating persistently larger LA size in G+ across the age spectrum.

Conclusion:
LV hypertrophy extent is similar across adult age groups in G+ HCM, while hypertrophy in G- HCM is milder in age groups <60 and similar to G+ HCM only at age >60. Although LA dilation is progressive with age in all HCM, G+ HCM exhibits greater LA dilation across the adult age spectrum.
Abstract 17178: Adverse Events in Endovascular Robotic Assisted Procedures
Authors: Sankaran Naveen Kumar , Rachakonda Sai Rakesh , Kocheril Abraham , Kapa Suraj , Kesavadas Thenkurussi
Published: July 2021

Introduction:
Endovascular procedures are traditionally performed for a variety of indications. However, guidewire/catheter manipulation and hazardous radiation exposure are limitations to manual interventions. Thus, significant work has been done to develop robotic approaches to therapies. These devices have FDA clearance for performing procedures like cardiac arrhythmias, angioplasty, aneurysm repair and stenting etc. With the increasing usage of robotic assistance in endovascular procedures, it is essential to understand the adverse events that may occur. This study aims to provide an understanding of adverse events with currently available robotic systems.

Methods:
The analysis of adverse events is performed with the FDA MAUDE (Manufacturer and User Facility Device Experience) database. MAUDE database is a collection of reports on medical devices reported by manufacturers, distributors, users, volunteers. In case of occurrence of adverse events, FDA regulations requires that event to be reported for further investigation. Based on the impact of events on the patient’s outcome, the reported events were grouped into 3 categories death (patient death), injury (patient injury) or device malfunction.

Results:
A total of 71 different events were reported collectively for all the four robotic devices (Hansen Medical- 37, Corindus Inc.-27, Stereotaxis Inc.-5 & Catheter Robotics Inc.-2). The major adverse events included death and common injuries such as perforation, pseudo-aneurysm / blockage/ tamponade/ clot, blood pressure dropped or an effusion, or hemodynamic instability. The table summarizes the events by brand of system.

Conclusions:
While robotic approaches to intervention reflect a potentially useful means to improve outcomes of endovascular procedures by optimizing catheter manipulation with finer robotic motions or limiting radiation exposure, there are potentially significant risks. Whether these reflect higher or lower risk than traditional manual approaches requires randomized studies. Use of robotic technologies may present additional risks in light of potential malfunctions that occur from system errors that a human system may not be prone to. Future studies will be needed to better understand incremental benefit.
Abstract 17189: Reprogramming of Fibroblasts Into Cardiac Progenitor Cells Using Crispr Activation System
Authors: Jiang Lin , Liang Jialiang , Huang Wei , Paul Christian , Wang Yigang
Published: July 2021

Background and Objective:
CRISPR tools that allow for precise manipulation of individual loci have not been used in generation of
i
nduced
c
ardiac
p
rogenitor
c
ells (
iCPC
s). This study was designed to determine the feasibility and effectiveness of reprogramming fibroblasts into iCPC using CRISPR activation (CRISPRa) system.

Methods:
Tail-tip fibroblasts (TTFs) were isolated from Nkx2-5 cardiac enhancer GFP reporter mice. A gRNA pool targeting 17 progenitor genes was synthesized and transduced with dCas9-VP64 lentivirus into TTFs (
Fig.1A
). The phenotype of iCPCs was then characterized by immunostaining and FACS of progenitor markers. Finally, the cardiac-lineage differentiation potential of iCPCs was determined by immunostaining and electrophysiological assay under defined induction mediums.

Results:
iCPCs with GFP expression were formed in TTFs after transduction of CRISPRa targeting
Isl1
,
Gata4
,
Baf60c
,
Tbx5
and
Nkx2-5
(Fig.1B), while GFP was not activated by control virus. Cardiac progenitor markers were activated in iCPCs as shown by immunostaining (Fig.1C). The generation efficiency of Flk1-postive iCPCs induced by CRISPRa was ~60% as showed by FACS. iCPCs can be differentiated into cardiomyocytes as identified by immunostaining of cardiac-specific markers (Fig.1D). The iCPC-derived cardiomyocytes displayed spontaneous beating and showed cardiac action potentials (Fig.1E).

Conclusion:
The CRISPRa system is an efficient and specific way to generate iCPCs, which could provide a novel source of cells for cardiac regenerative medicine.
Abstract 17199: Airway Mucociliary Clearance is Impaired After Infant Congenital Cardiac Surgery
Authors: Adams Phillip S , Corcoran Timothy , Czachowski Michael , Saville Al , Lin Ivy , Domnina Yuliya , Baust Tracy , Khalifa Omar , Zahid Maliha , Sanchez de Toledo Joan , Lo Cecilia W
Published: July 2021

Introduction:
A link between congenital heart disease and airway ciliary dyskinesia has been identified. Postoperative pulmonary dysfunction is highly prevalent after cardiac surgery and contributes to morbidity, mortality, and healthcare costs. We hypothesized that respiratory mucociliary clearance (MCC) would be impaired in the immediate postoperative period after infant congenital cardiac surgery.

Methods:
41 infants from 5-254 days old underwent MCC scans using nebulized technetium-99m sulfur colloid either immediate postoperative or later postoperative periods after congenital cardiac surgery. Physiologic variables and medications at the time of scan were recorded.

Results:
There was no significant correlation between MCC and age, gender, race or any of the of the physiologic variables, such as temperature, SpO2, or FiO2, at the time of the MCC scan. MCC was lowest on the first 2 postoperative days, increased at days 3-7, and highest beyond postoperative day 7 (Fig1). Fentanyl (p=0.023) and paralytics agents (p=0.018) were significantly associated with lower MCC, while benzodiazepines (p=0.447) and dexmedetomidine (p=0.675) showed no measurable impact (Table 1).

Conclusion:
We show for the first time, with quantitative measurements, the near absence of infant MCC in the immediate postoperative period after congenital cardiac surgery. This may be exacerbated by opioid exposure, which should be minimized. Our results further suggest sedative alternatives such as benzodiazepines and dexmedetomidine are preferable to help optimize infant airway clearance. This may reduce ICU length of stay and improve outcomes after cardiac surgery.
Abstract 17250: Underestimation of RV Volume by 3D Echocardiography in Patients With Severe PAH
Authors: Kubba Saad , Airhart Sophia , Wickstrom Kelly , Rosado-Toro Jose , Janardhanan Raj , Vanderpool Rebecca , Rischard Franz
Published: July 2021

Background:
Right ventricular (RV) volume is a significant predictor of mortality in pulmonary arterial hypertension (PAH). RV volume measured by 3D echocardiography (3DE) an attractive imaging modality because it is faster and cheaper than cardiac MRIs. However, newer semi-automated speckle tracking 3DE has not been validated against cardiac MRI (CMR) in patients with severe PAH and dilated RVs. This study investigated the feasibility of 3DE to measure RV volumes in a prevalent cohort of patients with severe PAH.

Methods:
Patients with severe PAH with a 3DE and CMR within 30 days were included. RV endocardial contours were performed using TomTec 4D RV analysis© for 3DE and Circle Cardiovascular Imaging 42© for CMR.

Results:
Patients (n = 11) had severe PAH as classified as having high sPAP (66.4±5.0 mmHg), and reduced RV ejection fraction as measured by CMR (37.7±2.9%). In two patients, 3DE was not obtainable due to suboptimal definition of ventricular walls. In the remaining patients, there were systematic underestimation of volumes by 3DE (EDV bias: -71.5 LOA: 63.7; ESV -58.7: LOA: 72.7) and appears to be volume dependent
(Fig 1A
). Lack of agreement seemed to possibly be related to extrapolation of poorly defined lateral wall RV endocardium by 3DE in patients with a large right ventricle
(Fig 1B).

Conclusion:
Lack of agreement between CMR and 3DE derived RV volumes suggests the need for further validation of 3DE in patients with severe PAH.
Abstract 17251: Visualization of Neural Crest Cell Migration to the Dorsal Surface of Developing Zebrafish Myocardium
Authors: Gudapati Varun , Ding Yichen , Langenbacher Adam D , Chang Chih-Chiang , Chen Jau-Nian , Hsiai Tzung K
Published: July 2021

Introduction:
Neural crest (NC) cells are involved in cardiac development, and NC defects account for over 10% of all congenital heart disease. The migratory and morphogenic patterns of these NC cells are not well understood because conventional optical microscopes struggle to acquire images of live embryos with sufficient temporal and spatial resolution without causing major photo-damage. To address these issues, the lab has designed and built a light-sheet fluorescence microscope (LSFM) that is capable of acquiring dual-channel signals with high spatial and temporal resolution.

Hypothesis:
We hypothesize that the LSFM system will capture heart tube development at a cellular level and show the time point and location at which the NC cells integrate with the heart tube.

Methods and Results:
The transgenic line that is manipulated for this study is the
Tg(neural crest:nfsB-mCherry, cardiac: eGFP)
in which the heart tube fluoresces green while NC-derived cells fluoresce red. 10 zebrafish were imaged using the 3-D time-lapse LSFM setup from 15 hours post fertilization (hpf) to 36 hpf. The imaging data was qualitative and consistent across fish. Fig. 1 (a) shows mCherry NC-derived cells (red) integrating with eGFP cardiomyocytes (green) and areas of colocalization (yellow). Fig 1 (b) and (c) show the time course of the NC cell migration into the heart tube. By 26-27 hpf, the NC cells contacted the dorsal surface of the heart tube. By the 29 hpf, the NC-derived cells integrated into the heart tube and expressed nuclear eGFP, which is visualized by the yellow fluorescing portions of the image.

Conclusions:
We conclude that the LSFM was successful in acquiring distinct signals from the heart tube cells and the NC-derived cells. The temporal and spatial resolution was sufficient to observe NC migration at the single cell level and map out exactly where along the heart tubule the NC-cells entered.
Abstract 17252: Left Ventricular Noncompaction in Patients With Preserved Ejection Fraction is Associated With Increased Cardiac Hospitalizations
Authors: Rambhujun Vikashsingh , Paruchuri Vijayapraveena , Hafiz Abdul Moiz , Kreatsoulas Catherine , DeLeon Joshua , Marzo Kevin , Gaztanaga Juan
Published: July 2021

Introduction:
Prominent left ventricular trabeculations or left ventricular non-compaction (LVNC) is observed now more often with cardiac magnetic resonance imaging (MRI). The significance of LVNC in patients with preserved ejection fraction remains unknown however it may be a precursor to cardiomyopathy.

Hypothesis:
This study is aimed to evaluate the clinical outcome of patients with LVNC and preserved LV function compared to patients with normal myocardial anatomy and function.

Methods:
This is a retrospective analysis of patients referred for cardiac MRI between October 2012 and July 2017. Patients with hypertrophic cardiomyopathy, ischemic heart disease and infiltrative heart disease were excluded. Patients with prominent trabeculations and a noncompacted to compacted myocardial ratio ≥ 2.3 with a preserved left ventricular ejection fraction of ≥ 50% were included. The primary outcome is defined as cardiac hospitalizations resulting from chest pain, arrhythmias, syncope, and congestive heart failure. These patients were compared to patients who underwent cardiac MRI with preserved function and normal myocardial anatomy.

Results:
There were a total of 39 patients who met criteria of LVNC with preserved function by MRI. These were compared to 59 patients with preserved function and normal myocardial anatomy on MRI. There was no significant difference in demographics and LV size and function between the groups. In comparison with the control group, the LVNC group had a mean age of 44 ± 14 versus 42 ± 16, 62% female sex versus 59%, LV EF of 59 ± 5% versus 62 ± 6%, LV end diastolic volume of 148 ± 26 ml versus 146 ± 40 ml. There were a total of 7 cardiac hospitalizations, of which 5 occurred in patients with LVNC. LVNC was associated with a greater than 4-fold increased risk of events (HR4.6, 95%CI 1.0-21.8) (figure)

Conclusions:
In patients with preserved EF, LVNC anatomy is significantly associated with increased cardiac hospitalizations.
Abstract 17280: A New in vivo Imaging Protocol for Non-Invasive Detection of Right Ventricular Dysfunction in a Pulmonary Hypertension Mouse Model
Authors: Hansen Thomas , Bubb Kristen , Figtree Gemma
Published: July 2021

Introduction:
Accurate measurements of right ventricular (RV) function are critical for studying novel therapies impacting the heart and pulmonary circulation. Until now, assessment in mouse models has relied on invasive measures. Improvements in mouse echocardiography may facilitate application of measures recently validated in humans, including tricuspid annular plane systolic excursion (TAPSE) and RV-S’ (systolic excursion velocity), to allow non-invasive assessment of RV function.

Aims:
To apply and validate TAPSE and RV-S’ using high-resolution echocardiography for the measurement of RV function in a mouse model of pulmonary hypertension (PH).

Methods:
Echocardiography was performed on mice 3 weeks after induction of PH using inhaled bleomycin or saline control. PAT, TAPSE and RV-S’ were recorded in mice using a 55-mHz transducer (Visualsonics, Vevo3100). Invasive measurements of right ventricular systolic pressure (RVSP) were obtained via catheterisation of the internal jugular vein, prior to culling.

Results:
RVSP was significantly elevated in bleomycin-treated mice (
33.41±0.8mmHg
n=10) compared to controls (
25.66±0.9mmHg
n=11; p<0.0001). Similarly, RV hypertrophy was observed in bleomycin mice
[RV:body weight
1.156±0.03g/kg
n=11] compared with control (
0.968±0.02g/kg
n=12; p=0.0002). TAPSE was sensitive to these differences, being significantly reduced in bleomycin mice (
0.5739±0.020mm
n=8) compared with control (
0.7387±0.033mm
n=10; p=0.0012), and correlated significantly with invasive RVSP (r
2
=0.7218; p<0.0001). RV-S’ was also reduced in bleomycin mice (18.14±0.98mm/s n=7) compared with control (25.38±1.24mm/s n=8; p=0.0006) and correlated strongly with RVSP (r
2
=0.6378; p=0.0011). The correlation of both TAPSE and RV-S’ with RVSP compared favourably to the previously used surrogate measure of RVSP in mice, PAT (r
2
=0.5278; p=0.0002).

Conclusions:
TAPSE and RV-S’ can be applied in mouse echocardiography, and are sensitive, non-invasive measures of PH and RV dysfunction, comparing well with gold-standard invasive right ventricular systolic pressures. This may benefit the power of future preclinical studies of novel therapies in pulmonary hypertension and RV dysfunction.
Abstract 17319: Distinct Effects of Human Calmodulinopathy on the Function of Small Conductance Ca
2+
-Activated K
+
(SK) Channels
Authors: Ledford Hannah A , Park Seojin , Muir Duncan , Smith Wen , Woltz Ryan L , Sihn Choong-Ryoul , Sirish Padmini , Yamoah Ebenezer N , Yarov-Yarovoy Vladimir , Zhang Xiao-Dong , Chiamvimonvat Nipavan
Published: July 2021

Background:
Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca
2+
-dependent ion channels. Mutations in CALM1, CALM2, and CALM3 have recently been linked to cardiac arrhythmias, such as Long QT Syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and familial idiopathic ventricular fibrillation (IVF). Small-conductance Ca
2+
- activated K
+
channels (SK) are voltage-independent channels that are regulated solely from beat-to-beat changes in intracellular calcium. CaM regulates the function of multiple ion channels, including SK channels, although the effect of CaM mutations on these channels is not yet understood. We hypothesize that human CaM mutations linked to sudden cardiac death disrupt SK channel function by distinct mechanisms.

Methods and Results:
We tested the effects of LQTS (CaM
D96V
, CaM
D130G
), CPVT (CaM
N54I
, CaM
N98S
), and IVF (CaM
F90L
) CaM mutants compared to CaM
WT
on SK channel function. Using whole-cell voltage-clamp recordings, we found that CaM
D96V
and CaM
D130G
mutants significantly inhibited apamin-sensitive currents. Similarly, action potential studies in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) also revealed significant knockdown of apamin-sensitive currents.

Immunofluorescent confocal microscopy confirmed that this effect was not due to changes in SK channel trafficking. Rather, co-immunoprecipitation studies showed a significant decrease in the association of these CaM mutants with the SK channel. Rosetta molecular modeling was used to identify a conformational change in CaM
F90L
structure compared to that of CaM
WT
.

Conclusions:
We found that CaM
D96V
and CaM
D130G
mutants significantly reduced apamin-sensitive currents, through a dominant negative effect on SK channel function. Consistent with our hypothesis, CaM
F90L
resulted in the least inhibitory effects. The data suggests that specific mutations with phenylalanine to leucine (CaM
F90L
) may disrupt the interaction between apo-CaM with CaMBD on the SK2 channel.
Abstract 17323: Polyinosinic-Polycytidylic Acid Primes Cardiac Progenitors From Human Induced Pluripotent Stem Cells for Enhanced Cell Therapy and Cardiomyocyte Maturation
Authors: Biermann Mitch , Cai Wenxuan , Lang Di , Hermsen Jack , Profio Luke , Shao Annie , Han Tianxiao , Woon Marites , Glukhov Alexey , Ge Ying , Kamp Timothy J
Published: July 2021

Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) hold promise for disease modeling, drug discovery, and therapy, but the challenge remains to create mature cardiomyocytes like those found in the adult heart. While groups have increased the maturity of hiPS-CMs in extended culture with electrical, metabolic, and mechanical stimulation, we hypothesized that epigenetic modulation during the formation of cardiac progenitors (hiPS-CPCs) could enhance their capacity to form mature CMs. We found that priming with the innate immune agonist polyinosinic-polycytidylic acid (pIC) decreased cardiac lineage-HDAC expression during the formation of hiPS-CPCs in defined small molecule monolayer differentiation. While both untreated and primed day 5 hiPS-CPCs contained equivalent >80% purity of KDR+PDGRFα+ CPC populations, gene expression studies using RNAseq demonstrated that pIC priming enhanced the early cardiogenic and Notch signaling programs. When both groups were differentiated in basal media, primed hiPS-CPCs gave rise to more mature cardiomyocytes based on larger cell size, increased optical action potential upstroke velocity, greater oxidative metabolism, enhanced sarcomere maturation, and upregulated transcriptional markers of CM maturation including cTnI, cardiac actin, and αMHC. These maturation effects of pIC treatment were blocked by the Notch inhibitor DAPT. Most impressively, primed hiPS-CPCs improved survival as well as myocardial systolic/diastolic function in a mouse model of myocardial infarction (Figure).

Conclusion:
pIC-primed hiPS-CPCs with the capacity to give rise to hiPS-CMs of enhanced maturation hold promise for improved disease modeling, drug screening and cell therapy.