bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2214: The Aptamer ARC1779 Is A Potent And Specific Inhibitor Of von Willebrand Factor (vWF) Mediated Ex Vivo Platelet Function In ST-elevation (STEMI) and non-ST elevation (NSTEMI) Acute Myocardial Infarction (AMI)
Authors: Jilma Bernd , Mayr Florian B , Spiel Alexander O , Merlino Patricia G , Marsh Harold N , Schaub Robert , Gilbert Jim
Published: July 2021

Background: ARC1779 is an aptamer which blocks the A1 domain binding of the vWF A1 domain to platelet GPIb receptors that is now in development for the treatment of AMI. vWF is increased in the elderly and in the setting of AMI, as reflected in higher vWF levels in circulation and in increased shear-dependent platelet function as measured by the platelet function analyzer (PFA-100) and cone and plate analyzer (IMPACT). Conventional therapy of AMI partially reduces platelet activation and aggregation, but does not address excessive vWF activity or platelet adhesion.

Methods: We studied the ex vivo dose response curves for ARC1779 on PFA-100 and IMPACT platelet function tests, agonist-induced platelet aggregation, and vWF activity (free A1 domain sites) of patients with AMI on standard treatment including aspirin and clopidogrel (n=40), young (n=20) and elderly controls (n=20).

Results: ARC1779 fully blocked collagen ADP induced platelet plug formation as measured by PFA-100 with an IC100 of ~ 1–2 mcg/mL with citrate anticoagulation, and 3–5 mcg/mL with hirudin anticoagulation. ARC1779 fully blocked shear-dependent platelet adhesion measured by the IMPACT analyzer with an IC100 of ~ 1 mcg/mL with citrate anticoagulation. In contrast to GPIIb/IIIa antagonists, ARC1779 did not inhibit platelet aggregation by ADP, collagen or arachidonic acid at concentrations (10mcg/mL) that fully inhibited vWF dependent platelet function. ARC1779 fully blocked vWF activity ex vivo with an IC90 of ~ 1 mcg/mL in young controls and 6 – 8 mcg/mL in STEMI and NSTEMI patients.

Conclusions: ARC1779 potently and specifically inhibits vWF activity and vWF dependent platelet function, even in the setting of AMI where vWF activity is increased. ARC1779 represents a novel therapeutic principle (vWF antagonism) and a novel therapeutic class (aptamers). Potent and specific inhibition of VWF makes ARC1779 a promising development candidate for patients with AMI.

Results
Abstract 2246:
Non-invasive
ablation of the Left Superior Pulmonary Vein-Left Atrial junction using stereotactic focussed radiation
Authors: Sharma Arjun , Maguire Patrick , Sumanaweera Thilaka , Wong Douglas , Marshall Richard , Fajardo Luis , Fogarty Thomas
Published: July 2021

Introduction:
High energy x-ray irradiation from a linear accelerator mounted on a robot arm has recently been used to produce ablation of cardiac tissue in swine. This device is currently used in patients for diverse indications requiring careful targeting, from tumors to trigeminal neuralgia.

Purpose:
This study was to determine if this method of energy delivery can be used to target potential arrhythmogenic sites such as the left superior pulmonary vein-left atrial junction.

Method:
Hanford-Sinclair mini-swine (40–70kg)(n=9) were studied under anesthesia. The animals underwent radiation (x-rays, 20 – 80 Gray) using a computer controlled robotic arm (Cyberknife) which focussed the x-ray beam on a preselected target. Targeting was done using either surgically implanted fiducials or fully non-invasively using a CT scan. A proprietary system was used to radiate the target while minimizing the dose to surrounding structures. Motion compensation was made for respiration during radiation, but no cardiac contractile motion compensation was made. The animals were then studied 4 – 8 weeks later with construction of cardiac voltage maps using CARTO (Biosense-Webster). Following this the animals were sacrificed and specimens taken for pathology.

Results:
All animals survived treatment. Radiation to the left superior pulmonary vein eliminated local electrograms with voltage less than 0.1mv. Pathology specimens showed histologic changes consistent with an area of discrete myocyte damage. There was no evidence of phrenic nerve injury.

Limitations:
This study was done in swine and human pulmonary vein response to this treatment is unknown. This model was arrhythmia free and the efficacy of this treatment for atrial fibrillation is unknown.

Conclusions:
Selective targeting of cardiac arrhythmogenic sites can be done using stereotactically focussed external radiation with respiratory motion compensation. The left superior pulmonary vein can be ablated without compensation for cardiac contractility.
Abstract 2257:
KCNJ2
Mutations in Patients Referred for Catecholaminergic Polymorphic Ventricular Tachycardia Gene Screening
Authors: Ruan Yanfei , Theilade Juliane , Memmi Mirella , Giuli Luciana D , Rizzi Nicoletta , Filho Fernando E Cruz , Napolitano Carlo , Priori Silvia G
Published: July 2021

Background
: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia (BVT). Andersen-Tawil syndrome (ATS1), which are mainly caused by
KCNJ2
mutations, phenocopies CPVT and may manifest the typical adrenergically mediated BVT. The purpose of this study was assess whether patients (pts) lacking periodic paralysis typical of ATS1 and diagnosed as CPVT because of BVT carry
KCNJ2
mutations.

Methods and Results
: Mutational analysis of
KCNJ2
was performed in 23
RyR2
and
CASQ2
genotype-negative CPVT pts with normal QT interval. Two novel missense mutations (S220I and T305I) were identified. Mutations were absent in >400 reference alleles. Both of the pts present exercise or isoproterenol induced BVT, baseline ECG with prominent U wave and mild facial abnormalities. In vitro characterization showed that no current is detectable when S220I and T305I mutants clones are expressed; on the contrary co-expression of WT and mutant
KCNJ2
to mimic heterozygosis present in patients, caused significant dominant negative effect (see figure

). Confocal laser microscopy revealed normal sarcolemmal localization of the mutant channels and of the heterozygous channels.

Conclusions
:

KCNJ2
mutation with loss of function are present in a minority of pts with clinical diagnosis of CPVT.

Given the limited number of CPVT pts with
KCNJ2
mutations it is impossible to determine whether their prognosis is identical to that of
RyR2
and
CASQ2
related CPVT.

Screening of
KCNJ2
should be considered in CPVT pts without mutations in
RyR2
and
CASQ2
genes.
Abstract 2266: Development of Tricuspid Regurgitation Late After Left-Sided Valve Surgery in Patients without Significant Preoperative Tricuspid Regurgitation :A Single-Center Experience with Long-term Echocardiographic Examinations
Authors: Kwak Jae-Jin , Kim Min-Kyung , Kim Hyung-Kwan , Park Jin-Shik , Kim Kyung-Hwan , Kang Hyun-Jae , Koo Bon-Kwon , Kim Sang-Hyun , Chae In-Ho , Ahn Hyuk , Sohn Dae-Won , Oh Byung-Hee , Park Young-Bae , Choi Yun-Shik , Kim Yong-Jin
Published: July 2021

Aim:
We investigated the incidence and predictors of tricuspid regurgitation (TR) development long after left-sided valve surgery in patients without significant preoperative TR.

Methods:
Of 615 patients who underwent surgery for left-sided valve disease between 1992 and 1995, 335 patients without preoperative TR who completed at least 5 years of clinical and echocardiographic follow-up were enrolled. Late significant TR development was assessed by echocardiography with a mean follow-up duration of 11.6 ± 2.1 years.

Results:
Significant late TR was found in 90 patients (26.9%). Patients with late TR showed; an advanced age, a higher prevalence of atrial fibrillation and prior valve surgery, and a greater left atrial dimension. In addition, late TR was more frequent in patients with mitral valve surgery. Systolic pulmonary artery pressure and mean right atrial pressure were not different between the groups. Multivariate analysis showed that the preoperative atrial fibrillation (OR 5.37; 95% CI. 2.71–10.65; p<0.001) was the only independent factor of late TR development. Patients that developed late TR had a lower event-free survival rate than those that did not (p=0.03).

Conclusion:
The development of significant TR long after left-sided valve surgery is not uncommon and is associated with a poor prognosis. The preoperative atrial fibrillation is an independent predictor of the late TR.

Main Clinical and Echocardiographic Characteristics According to the Presence of Significant Late TR
Abstract 2269: Exogenous Sulfide Limits Inflammation in Response to Myocardial Ischemia - Reperfusion Injury
Authors: Sodha Neel R , Clements Richard T , Feng Jun , Liu Yuhong , Bianchi Cesario , Szabo Csaba , Stahl Gregory L , Sellke Frank W
Published: July 2021

Introduction
: Hydrogen sulfide (H
2
S) is produced endogenously in response to myocardial ischemia and thought to be cardioprotective. The mechanism underlying this protection has yet to be fully elucidated, but may be related to the ability of sulfide to limit inflammation. This study investigates the cardioprotection provided by exogenous H
2
S, generated as sodium sulfide, and its potential anti-inflammatory mechanism of action.

Methods
: The mid-LAD coronary artery in 12 Yorkshire swine was acutely occluded for 60 min, followed by reperfusion for 120 min. Controls (6) received placebo, and treatment animals (6) received sulfide 10 min prior to reperfusion. Hemodynamic, global, and regional functional measurements were obtained. Evans blue and TTC staining identified the area at risk (AAR) and infarction. Coronary microvascular reactivity was assessed. Tissue was assayed for myeloperoxidase (MPO) activity and inflammatory cytokines.

Results
: Pre-I/R hemodynamics were similar between groups, whereas post-I/R mean arterial pressure (mmHg) was reduced by 28.7±5.0 in controls vs. 6.7±6.2 in treatment animals (p<0.05). +LV dP/dt (mmHg/sec) was reduced by 1325±455 in controls vs. 416±207 in treatment animals (p<0.05). Segmental shortening in the AAR was better in treatment animals. Infarct size (% of AAR) in controls was 41.0±7.8% vs. 21.2±2.5% in the treated group (p<0.05). Tissue levels of IL-6, IL-8, and TNFα (see Table

) and MPO activity decreased in the treatment group (0.0025±0.003 vs. control 0.0397±0.016 units/mg protein (p<0.05)). Treated animals demonstrated improved microvascular reactivity.

Conclusions
: Sodium sulfide provides significant protection in response to I/R injury, improving myocardial function, reducing infarct size, and improving coronary microvascular reactivity, potentially through its anti-inflammatory properties. Exogenous sulfide may have therapeutic utility in clinical settings in which I/R injury is encountered.

Myocardial Levels of Inflammatory Cytokines
Abstract 2278: Isoform Specific PKC Responses Modulate ET-1 and Hypoxia Reperfusion Induced Injury
Authors: Ramzy Danny , Tumiati Laura C , Sheshgiri Rohit , Jackman Jessica , Badiwala Mitesh , Tepperman Elissa , Rao Vivek
Published: July 2021

Background:
Hypoxia and reperfusion (H/R) injury is a predominant cause of allograft failure following heart transplantation. Several investigators have shown that endothelin-1 (ET) reduces myocardial function and survival via modulation of protein kinase C (PKC). We examined the role of ET and PKC modulation on human saphenous vein endothelial cells (HSVEC).

Methods:
HSVEC were submitted to 24 hours of hypoxia (PO
2
<0.1%) and 24 hour of reperfusion (PO
2
=21%). Normoxic controls were incubated at PO
2
=21%. Cells were incubated with either ET:100nM, BOS (ET antagonist):10μM, ET+BOS or PBS during H/R. Cells were also treated with PKCδ, PKCλ and PKCϵ inhibitors. Caspase activity was measured. Free radical (ROS) and NO production were measured. Protein expression and translocation of PKC isoforms and eNOS were assessed using Western Blot analysis.

Results:
Apoptosis (35% increase in caspase 3,8,9 activity) was observed following H/R compared to normoxia. BOS therapy prevented apoptosis while ET exposure increased caspase activity by 75%, p<0.01. H/R resulted in PKCδ and ϵ translocation while reducing PKCλ activity. BOS exposure prevented H/R induced PKCδ and ϵ activation and PKCλ inhibition while incubation with ET enhanced H/R induced PKC effects. PKCδ and ϵ inhibition reduced caspase activity after H/R and abrogated ET induced apoptosis, p<0.01. PKCλ inhibition enhanced apoptosis. NO production was impaired following H/R, p<0.05. BOS therapy restored NO homeostasis while ET exposure worsened NO production compared to H/R alone, p<0.05. PKCδ and ϵ inhibition improved NO production while PKCλ inhibition worsened NO release. H/R driven ROS production was inhibited by BOS and enhanced by ET exposure, p<0.01. PKCλ inhibition raised ROS production while PKCδ and ϵ inhibition reduced ROS release, p<0.01. eNOS protein expression was reduced by H/R while BOS treatment prevented downregulation.

Conclusions:
Our findings revealed that ET plays a crucial role in cellular injury following H/R via specific PKC isoforms. ET via PKC modulation leads to endothelial dysfunction and cell death. Therefore, targeted isoform specific PKC modulation as well as BOS may prove to be optimal strategy to prevent endothelial injury during allograft storage and transplantation.
Abstract 2284: Non-invasively Determined Ventricular Elastance as a predictor of cardiovascular mortality in Patients With acute myocardial infarction and Preserved ejection fraction: Data from Infarction Prognosis Study (IPS) registry
Authors: Kim Sung Ai , Ha Jong-Won , Kim Hyeon Chang , Park Sungha , Choi Eui-Young , Shin Mi-Joo , Park Yoon-Jin , Choi Donghoon , Jang Yangsoo , Chung Namsik
Published: July 2021

Background
: Previous studies of the prognosis of myocardial infarction (MI) have focused primarily on patients with left ventricular (LV) systolic dysfunction. Little is known about the prognosis of patients with MI and preserved ejection fraction (EF), which is increasing. Since the ratio of mitral inflow (E) and annular velocity (E′) to stroke volume (E/E′/SV) has been reported as an index of diastolic elastance (Ed), we hypothesized that Ed has prognostic implication in patients with acute MI and preserved EF.

Method
: Between May 2005 and January 2007, a total of 421 patients with acute MI were prospectively enrolled in Infarction Prognosis Study (IPS) registry. Among 358 patients who had comprehensive echocardiographic study, 42 patients with significant valvular heart disease or coexisted cardiomyopathy and 50 patients with decreased EF (<40%) were excluded. This left a total of 266 patients, who constituted the study population. The primary end-point was cardiovascular mortality.

Results
: Median follow-up duration was 12 months. Of 266 patients, cardiovascular death occurred in 11 (4.1%) patients. Age (p< 0.001), LA volume index (p=0.001), the severity of diastolic dysfunction (grade ≥ 2, p=0.04), Ed (p=0.003) were univariate predictors of cardiovascular mortality. However, in multivariate Cox regression analysis, age (p=0.008, HR; 1.14, 95% CI; 1.03–1.25) and Ed (p=0.009, HR; 1.72, 95% CI; 1.14 –2.58) were found to be independent predictors for cardiovascular mortality in patients with acute MI and preserved EF. Cut-off value of Ed for cardiovascular mortality determined by Kaplan-Meier method (p<0.001 by log-rank test) and ROC curve (AUC 0.87, sensitivity 90%, specificity 74%) was 0.25.

Conclusion
: Non-invasively determined ventricular diastolic elastance is a novel and powerful independent predictor of cardiovascular mortality in patients with acute MI and preserved EF.
Abstract 138: Transient Receptor Potential Channel C1 Deficiency Protects the Murine Heart from Pressure Overload
Authors: Seth Malini , Zhang Zhu-Shan , Mao Lan , Burch Jarrett , Graham Victoria , Rockman Howard A , Birnbaumer Lutz
Published: July 2021

Transient receptor potential canonical (TRPC) channels are non-selective cation channels that are activated in response to G-protein coupled receptor activation, depletion of internal stores and mechanical stretch. Recent reports suggest that cardiac TRPC channels mediate calcineurin dependent cardiac hypertrophy, yet few details exist as to the mechanism for activation of these channels. Here, we provide evidence that TRPC1 channels are the dominant TRPC channel in mouse cardiomyocytes and cardiac TRPC1 protein expression is augmented by seven fold following thoracic aortic banding (TAC). In addition, we provide the first loss of function studies to show that mice lacking TRPC1 channels developed significantly less cardiac hypertrophy following pressure overload induced by thoracic aortic banding suggesting that TRPC1 may confer deleterious calcium entry. Whole cell voltage clamp studies of isolated adult cardiomyocytes reveal a non-selective cation current that is induced by pressure overload that is absent in TRPC1−/− cardiomyocytes and in which TRP blockers such as gadolinium, 2-amino biphenyl boric acid and
SKF96365
inhibit the TAC induced current. Finally, neonatal cardiomyocytes lacking functional TRPC1 display reduced TRPC current in response to cell stretch or angiotensin-II; the functional consequence of which includes reduced calcium oscillation frequency and reduced BNP expression. These results provide the first loss of function evidence for TRPC1 channels in cardiac hypertrophy and implicate TRPC1 as a stretch activated channel.
Abstract 339: Endogenous Muscle Atrophy F-box is a Positive Mediator of Cardiac Hypertrophy and Dysfunction in Response to Pressure Overload
Authors: Usui Soichiro , Hong Chull , Gao Shumin , Sadoshima Junichi
Published: July 2021

Muscle atrophy F-box (MAFbx, Atrogin-1) is an E3 ubiquitin ligase which plays a critical role in mediating skeletal muscle atrophy. It has been shown that cardiac specific expression of MAFbx inhibits pressure overload-induced cardiac hypertrophy, suggesting that MAFbx negatively regulates cardiac mass when overexpressed. To elucidate the role of endogenous MAFbx in regulating cardiac mass, we applied transverse aortic constriction (TAC) to MAFbx −/− and wild type (WT) mice. Pressure gradients in both groups were comparable (MAFbx −/− 90.4 mmHg vs WT 79.3 mmHg). In WT mice, protein expression of MAFbx in the heart was significantly increased (3.5 fold) after 2 weeks of TAC. Unexpectedly, left ventricular weight/body weight (LVW/BW) was significantly smaller in MAFbx −/− than in WT mice (4.49 vs 5.58, p < 0.01). The echocardiographically determined LV posterior wall thickness (1.00 vs 1.13 mm, p < 0.05) and LV mass index (151 vs 193, p < 0.05) after TAC were significantly smaller in MAFbx −/− than in WT mice, consistent with the notion that MAFbx −/− mice develop less hypertrophy in response to TAC. Lung weight/BW after TAC was significantly increased compared with the sham operated group in WT (10.1 vs 5.1, p < 0.01) but not in MAFbx −/− mice (6.0 vs 4.9, NS), suggesting that LV dysfunction after TAC was inhibited in MAFbx −/− mice. Furthermore, picric acid-Sirius red staining revealed that there was significantly less interstitial fibrosis after TAC in MAFbx −/− than in WT mice. These results suggest that MAFbx is up-regulated in response to pressure overload, and that the absence of endogenous MAFbx decreases hypertrophy and interstitial fibrosis and maintains cardiac function. In conclusion, distinct from its essential role in skeletal muscle atrophy, and also in direct contrast to the results seen with mice overexpressing MAFbx, endogenous MAFbx in the heart promotes cardiac hypertrophy and dysfunction during pressure overload.
Abstract 341: Both Beta-1 and Beta-2 Adrenergic Receptors (ARs) are Required for Pressure Overload Cardiac Hypertrophy
Authors: Zhao Mingming , Wagner Roger , Fajardo Giovanni , Urashima Takashi , Farahani Sara , Kobilka Brian K , Quertermous Thomas , Bernstein Daniel
Published: July 2021

In isolated myocytes, hypertrophy induced by norepinephrine is mediated via β-ARs, however, in vivo, mice with deletions of both major cardiac β-ARs still develop hypertrophy with pressure overload. The mechanism by which the heart adapts to pressure overload, producing either adaptive or maladaptive remodeling is still not completely understood. To study the role of β-ARs in pressure overload hypertrophy, we performed transverse aortic constriction (TAC) in congenic mice with targeted deletions of β1, β2 and both β1 and β2-ARs and in sham controls. After 3 wks, β1−/− mice showed a 21% increase in heart weight to body weight ratio (HW/BW) vs. sham, similar to WT (HW/BW 5.02 ± 0.72 for β1−/− vs. 5.20 ± 0.92 for WT). β2−/− mice showed an exaggerated (49%) hypertrophic response (HW/BW 5.81 ± 0.53, p < 0.001 vs. WT). Only when both β-ARs were ablated was hypertrophy fully attenuated: in β1β2−/− mice HW/BW increased only 8% (HW/BW 4.30 ± 0.31, p < 0.01 vs. WT). Echocardiography showed that peak band gradient was not different between groups (WT 45.3 ± 4.1, β1−/− 47.2 ± 10.2, β2−/− 49.0 ± 9.7, β1β2−/− 53.2 ± 11.3 mmHg) and all groups maintained normal LV function. Morphometric analysis confirmed the absence of hypertrophy in the β1β2−/−: mean cross-sectional area for WT was 254.7 ± 34.9 vs. β1β2−/− 115.8 ± 16.7μm
2
, which was not different from sham. Gene microarray analysis detected a set of genes which were differentially expressed in β1β2−/− vs. WT, β1−/−, or β2−/−:

S100 calcium binding protein A9/calgranulin B (S100a9, 4.5-fold up);

Cyclin-dependent kinase inhibitor 1A/P21 (Cdkn1a, 3.8-fold up);

Metallothioneins Mt1 (3-fold up) and Mt2 (2.7-fold up);

FK506 binding protein 5, a glucocorticoid receptor-regulating co-chaperone and calcineurin inhibitor (3.2-fold up).

In contrast, TGFβ2 was upregulated in WT, β1−/− and β2−/− but not in β1β2−/−. Differentially regulated genes were validated by SYBR QRT-PCR on the same RNA samples. Thus, β2-AR signaling may serve to limit the hypertrophic response to pressure afterload. However, both β-ARs are required for the development of a normal hypertrophic response. Ablation of both β-AR subtypes alters expression of several genes, some of which may be critical to the hypertrophic program.
Abstract 2292: Torsional Deformation Delay: a Novel Echocardiographic Index of Left Ventricular Peak Rotation Sequence Between Basal and Apical Level.
Authors: Chrzanowski Lukasz , Uznanska Barbara , Plewka Michal , Lipiec Piotr , Drozdz Jaroslaw , Krzeminska-Pakula Maria , Kasprzak Jaroslaw D
Published: July 2021

Purpose: left ventricular (LV) torsion (TOR) results from oppositely directed rotation (ROT) at the basal (BAS) and apical (AP) level. Speckle Tracking Echocardiography (STE) allows TOR assessment, but little is known of LV ROT temporal distribution. The aim was to evaluate the sequence of BAS and AP level ROT and to identify associated echocardiographic parameters.

Methods: 48 patients (PTS) were studied (mean age 54±13 years, 23 men). LV systolic function was normal in 23 PTS (LVEF 60% or more), and various degrees of dysfunction were present in 25 PTS (mean LVEF 40±10%). Digital short axis loops at BAS and AP level were analyzed using STE algorithm to measure ROT in degrees (°). After adjustment for heart rate, Torsional Deformation Delay (TDD) was calculated as the difference between the time from the onset of QRS complex to the peak average systolic ROT at BAS and AP level (figure

).

Results: mean TOR, BAS ROT and AP ROT was 14.3±7.3°, −6.8±4.7° and 7.5±6.1° respectively. Mean TDD was 19±107 ms (range from −285 to 248 ms); negative TDD indicated shorter time to BAS peak ROT. No difference of mean TDD was found between PTS with normal and decreased LVEF. TDD outside the range of −28 ms to 28 ms, derived by ROC analysis, was shown to have 96% specificity in detecting PTS with LVEF <60%. It was also associated with higher LV mass index as compared to TDD ranging from −28 to 28 ms (130 g/m2 vs 100 g/m2, p=0.025).

Conclusions: a novel TDD index allows evaluation of LV ROT temporal distribution between BAS and AP level. TDD values outside the range of −28 ms to 28 ms are associated with decreased LVEF and presence of LV hypertrophy. Further studies are required to assess the role of TDD in cardiac imaging.
Abstract 2303: Prospective Correlation of Echocardiography Findings with Hematologic and Pulmonary Function Parameters in Children with Sickle Cell Disease
Authors: Dham Niti , Sable Craig , Minnitti Caterina P , Campbell Andrew , Arteta Manuel , Winnie Glenna , Rana Sohail , Darbari Deepika , Oneykwere Onyinye , Kato Gregory J , Gladwin Mark T , Castro Oswaldo L , Gordeuk Victor R , Ensing Gregory
Published: July 2021

Background
Adults with sickle cell disease (SCD) have an increased prevalence of pulmonary hypertension (PAH), associated with significant morbidity and mortality. This finding has not been validated in children. We carried out a prospective comparison of echocardiography (echo) data between SCD and control patients and a correlation between echo findings and hematologic and pulmonary function testing (PFT) in SCD patients.

Methods
Children with SCD and age and gender matched controls were prospectively enrolled during well visits. Each subject underwent a history and examination, echo, hematologic testing, and PFT. Echo data was compared between SCD patients and controls, and regression analysis was performed to assess for correlation between echo parameters and anemia, markers of hemolysis, and PFT in SCD patients.

Results
Of the 194 SCD patients and 29 controls enrolled, 180 SCD patients and 26 controls had measurable tricuspid valve regurgitation (TR) to estimate systolic pulmonary pressure. TR, left ventricle (LV) size and LV mass were significantly higher in children with SCD (Table 1

). Linear regression analysis in SCD patients showed that TR, LV size, LV mass, and diastolic function (E/E
TDI
) correlated significantly with hemoglobin, markers of hemolysis, and obstructive pulmonary disease (Table 2

). There was no correlation between echo parameters and age, blood pressure, or measures of restrictive lung disease

Conclusion
Children with SCD have higher estimated pulmonary pressure, LV size and mass and a trend toward worse diastolic function when compared to controls. TR and LV size and mass correlate with anemia, hemolysis, and obstructive patterns on PFT.

Table 1 -

Comparative Data

Table 2 -

Regression Analysis
Abstract 2319: Genetic Variations Of
Mrf-2/Arid5b
Confer Risk Of Coronary Artery Disease And Diabetes Mellitus In The Japanese Population
Authors: Wang Guoqin , Watanabe Masafumi , Imai Yasushi , Hara Kazuo , Manabe Ichiro , Maemura Koji , Matsumoto Sahohime , Horikoshi Momoko , Kadowaki Takashi , Yamazaki Tsutomu , Nagai Ryozo
Published: July 2021

Mrf-2/Arid5b, a member of AT-rich interaction domain family of transcription factors, is highly expressed in the cardiovascular system and is believed to play essential roles in the phenotypic change through its regulation of smooth muscle cell differentiation. In addition, recent studies on gene-engineered mice suggested that this transcriptional factor is involved in obesity and adipogenesis, which are critical aspects of metabolic syndrome and diabetes mellitus. Thus, we hypothesized that genetic variations of the Mrf-2 gene may be associated with susceptibility to coronary artery disease (CAD) and diabetes mellitus (DM). To examine the association between Mrf-2 polymorphisms and CAD, we investigated 17 common SNPs of Mrf-2 in 475 CAD subjects and 310 control subjects. Four nearby SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) showed almost complete linkage disequilibrium, and disease associations were revealed not only for individual SNPs (
P
=0.0002, rs2893880;
P
=0.0067, rs7087507, respectively) but also for their haplotype combination (
P
=0.04, G-C-G-A (rs2893880-rs10740055-rs7087507-rs10761600)). Furthermore, these positive disease associations still existed after logistic regression analysis was performed to eliminate confounding conventional coronary risk factors. Subsequent analysis revealed that the aforementioned SNPs also statistically conferred risk of DM. To confirm these findings, we recruited another 500 DM subjects and 500 control subjects, and assessed the same haplotype block for their disease associations. Consistent significant associations were observed (
P
=0.0238, rs2893880;
P
=0.0014, rs10740055;
P
=0.0067, rs7087507;
P
=0.0022, rs10761600;
P
=0.0031 and
P
=0.04, C-A-A-T and G-C-G-A (rs2893880-rs10740055-rs7087507- rs10761600), respectively). Moreover, the disease-associated genotypes were also revealed to be correlated with the level of serum adiponectin, which is known as an anti-diabetic adipocytokine. . In conclusion, our study implicates genetic variations of Mrf-2 as previously unknown genetic risk factors for CAD and DM. We believe that the associations of Mrf-2 with CAD may be mediated at least partly via its associations with DM.
Abstract 2321:
CXCL5
Genotype is Associated with Mortality after Acute Coronary Syndromes
Authors: Beitelshees Amber L , Zineh Issam , Cresci Sharon , Wu Jun , Minton Matthew R , Province Michael A , Spertus John A
Published: July 2021

BACKGROUND: Epithelial neutrophil activating peptide (ENA-78) is a chemokine implicated in many inflammatory processes and may be involved in cardiovascular disease. We have previously found the −156 G>C variant in the ENA-78 gene (
CXCL5
) to be associated with elevated plasma ENA-78 concentrations and production from cultured leukocytes. Since leukocytes, including neutrophils, are involved in acute cardiovascular events, we hypothesized that the
CXCL5
−156 G>C variant would be associated with worse event-free survival after acute coronary syndromes (ACS).

METHODS: A prospective cohort of ACS patients (n=704) with 3-year follow-up was assessed and
CXCL5
was genotyped by Taqman. Cox proportional hazards models adjusting for age, race, sex, diabetes, heart failure, ACS type, coronary revascularization, and genotype were constructed in the entire cohort and separately by race. Kaplan Meier curves were estimated.

RESULTS: The −156C allele frequency was 0.17, 0.12, and 0.43 in the overall cohort, whites, and blacks, respectively. The −156C allele was associated with an increased risk mortality according to a recessive model of inheritance in the overall cohort (HR 2.8, 95% CI 1.4 –5.9) [Figure

], and in the white (HR 3.7, 95% CI 1.3–11.1) and black (HR 2.6, 95% CI 0.90 –7.3) subgroups.

CONCLUSIONS:
CXCL5
−156 C/C genotype was associated with 2.8-fold higher mortality relative to other genotypes in ACS patients. The magnitude of risk was similar in both white and black patients. Taken with previous findings,
CXCL5
genotype may represent a novel risk-stratification biomarker in ACS.
Abstract 2335: Transposition Of The Great Arteries And Double Outlet Right Ventricle Have Related Early Developmental Origins: Fundamental Insights From
In Vivo
Imaging
Authors: Phoon Colin K , Ji Ruiping , Chowdhury Piyali Dhar
Published: July 2021

Congenital heart defects (CHD) are the most common birth defect. Proper retinoic acid (RA) signaling is required for normal development, and RA excess produces conotruncal CHD such as transposition of the great arteries (TGA) and double outlet right ventricle (DORV). We hypothesized that origins and evolution of TGA and DORV follow specific developmental patterns, definable
in vivo
by noninvasive ultrasound biomicroscopy (UBM)-Doppler imaging. Timed-pregnant ICR mice were injected with 70 mg/kg IP RA at 8.5 days post-conception (E8.5). Individual embryos were tracked with 40 MHz UBM-Doppler longitudinally on 5 consecutive days (E11.5–15.5: N=34 injected, N=8 uninjected controls). CHD included TGA (24%) and DORV (21%, all with right aorta, left pulmonary artery), as well as ventricular septal defect (VSD, defined at E15.5) and double-inlet left ventricle. External gross examination and histology confirmed ~90% concordance of UBM diagnosis of CHD, here (at E15.5) and in separate experiments (E11.5–15.5, N=111). All E11.5 embryos showed normal cardiac looping, with a normal unseptated heart and outflow tract (OFT) - the truncus arteriosus -arising from the right ventricle/bulbus cordis. Of embryos destined for TGA, 7/8 showed partial septation of the distal truncus into parallel OFT at E12.5; 4 showed DORV at E12.5 before evolving into TGA by E13.5. Of embryos destined for DORV, 6/7 showed partial septation of the distal truncus into parallel OFT at E12.5 as well. Thus, abnormal septation commences in the more distal truncus arteriosus as early as E12.5. In contrast, embryos destined for normal OFT development showed partial OFT septation in spiral (non-parallel) fashion, with complete/near-complete OFT septation and morphology at E13.5. All TGA/DORV embryos displayed normal cardiac function.

CONCLUSIONS.
TGA and DORV are developmentally related, differing only in complete (TGA) vs. incomplete (DORV) leftward truncal shift. Given normal heart, proximal OFT, and cardiac function, flow streams do not explain TGA/DORV morphogenesis. Corresponding to 4–6 weeks’ human gestation, these first
in vivo
data support longstanding hypotheses of TGA/DORV embryogenesis, and implicate RA signaling in the pathogenesis of abnormal truncal septation and shift.
Abstract 2346: Stenting of Pulmonary Artery Branch Stenosis Alleviates Pulmonary Valve Insufficiency in a Swine Model of Repaired Tetralogy of Fallot
Authors: Petit Christopher J , Gillespie Matthew J , Harris Matthew A , Seymour Travis L , Liu Timothy Y , Khan Azeem R , Kim Richard , Rodriguez Evelio , Gaynor J. W , Rome Jonathan J
Published: July 2021

Introduction
: Pulmonary insufficiency-induced right ventricular volume overload in adults with repaired tetralogy of Fallot (TOF) is associated with reduced exercise tolerance, ventricular arrhythmias and sudden cardiac death. Studies have shown that the severity of pulmonary insufficiency (PI) predicts these symptoms. There has been indirect evidence that pulmonary artery branch stenosis (PABS) exacerbates PI in adults with repaired TOF. However the impact of treatment of PABS on PI has not been evaluated.

Hypothesis
: Relief of unilateral PABS in the setting of PI alleviates the severity of PI.

Methods
: Newborn piglets (n=9) underwent pulmonary valve resection with transannular patch and left pulmonary artery (LPA) banding. Between 10 to 16 weeks later, a cardiac catheterization was performed with hemodynamic evaluation and stenting of the banded LPA. Immediately prior to catheterization, and then 1 week following intervention, a cardiac MRI was performed. MRI data obtained included main and branch pulmonary arterial forward and reverse flow, and right and left ventricular volume.

Results:
Six animals survived the protocol. At time of catheterization, the LPA had a discrete stenosis, with a mean gradient of 11.6 mmHg (range 9 –16.1) across the banded region. The mean diameter of the LPA at the banded region was 3.4 mm (range 3.1– 4.2) and 10.8 mm distally (range 9.6 –14) at baseline, compared with a mean right pulmonary artery diameter of 20.2 mm. The banded region was stented to a mean diameter of 10.4 mm (range 8 –12.6). The main pulmonary artery regurgitant fraction (RF) at baseline was a mean of 38.2%; after stenting of the LPA, the RF decreased to 29.6% (p=0.02). Flow into the LPA improved in all animals, from a mean of 12.2% of total at baseline to 33.6% following stenting (p<0.01). While the total RF decreased following LPA stenting, the branch pulmonary arterial RF did not change significantly for either pulmonary artery. Right ventricular volume did not change significantly after stenting of the LPA.

Conclusions:
In the setting of unilateral PABS, stenting alleviates the severity of PI in an animal model of repaired TOF. Though clinical studies are required, these findings should be considered in decisions regarding treatment of PABS after repair of TOF.
Abstract 2349: Cryoablation for Atrioventricular Nodal Reentrant Tachycardia (AVNRT) in 154 Young Patients: 4mm vs. 6mm Catheter Tip Sizes
Authors: Chanani Nikhil K , Chiesa Nancy A , Dubin Anne M , Avasarala Kishor , Van Hare George F , Collins Kathryn K
Published: July 2021

Introduction
: Cryoablation of AVNRT has a high initial success rate and an excellent safety profile; however, there is a risk of recurrence. We hypothesized that the transition from a 4mm to a 6mm cryoablation catheter tip size would decrease recurrences without compromising safety.

Methods/Results
: We retrospectively reviewed all patients (n=154) who underwent cryoablation for AVNRT at the UCSF/Stanford Pediatric Arrhythmia Center from 1/04 –2/07. Initially, we used the 4mm tip, and then transitioned to a 6mm tip except for younger and smaller children. The majority of the patients had a structurally normal heart. 10 patients had congenital heart disease (3 ASDs, 3 aortic valve abnormalities, 1 Ebstein’s, 1 PDA, 1 unbalanced AV canal defect, 1 L-TGA). Typical AVNRT was inducible in 123 patients (80%), atypical in 13 (9%), and both typical and atypical in 1 patient. 17 (11%) had presumed AVNRT. Additional arrhythmias were documented in 18 patients (7 WPW, 6 AET, 4 atrial fibrillation, 1 JET). There was no difference in initial outcomes between the 4mm and 6mm tips. There was no permanent AV block. Recurrence rates were lower with the 6mm tip, but this did not reach statistical significance. The median time to recurrence was 2 (0.25–20) months. Follow-up time was longer in the 4mm group but did not significantly impact recurrence rate (p=0.61). Recurrences were not associated with any patient variable (age, size, heart disease, AVNRT inducibility, additional arrhythmias) or any procedural variable (fluoroscopy time, duration of cryoablation, transient AV block, presence of residual slow AV nodal pathway or echo beats).

Conclusions
: Initial outcomes of the 6mm cryoablation catheter tip for AVNRT are excellent and early recurrence rates are promising. However, we have yet to demonstrate a convincing advantage for the 6mm tip. Further improvements in cryoablation technique are necessary to reduce recurrences without sacrificing the safety profile.

Cryoablation for AVNRT
Abstract 2356: Dual Antiplatelet Therapy following Percutaneous Coronary Intervention with Stent Implantation in Patients on Chronic Oral Anticoagulation
Authors: Rogacka Renata , Chieffo Alaide , Michev Iassen , Airoldi Flavio , Latib Azeem , Cosgrave John , Montorfano Matteo , Carlino Mauro , Sangiorgi Massimo G , Castelli Alfredo , Magni Valeria , Godino Cosmo , Aranzulla Tiziana , Colombo Antonio
Published: July 2021

Objectives:
To evaluate the safety of dual antiplatelet therapy in patients in whom long-term anticoagulation (AC) with warfarin is recommended.

Background:
It is well established that antiplatelet therapy with aspirin ad thienopiridines is required following percutaneous coronary intervention (PCI) with stent implantation. Some patients have also indication for long-term AC. The optimal antithrombotic strategy following PCI in such patients is unclear.

Methods:
All consecutive patients who underwent PCI with stent implantation discharged on triple therapy (defined as the combination of aspirin and thienopyridines and AC with warfarin) were analyzed.

Results
One-hundred and twenty-seven patients with 224 lesions: 86.6% males, mean age 69.9±8.8 years were included in the study. Drug-eluting stents (DES) were positioned in 71 (55.9%) and bare metal stent (BMS) in 53 (41.7%) patients. Atrial fibrillation (AF) was the main indication (59.1%) for AC treatment, followed by prosthetic valves (12.4%) and mural left ventricular (LV) thrombus (9.1%). Average risk of thromboembolic events in the subgroup with AF was 1.79 ± 1.23 according to CHADS2 score. The mean triple therapy duration was 5.6±4.6 and clinical follow-up 21.0±19.8 months. During the triple therapy period, 6 patients (4.7%) developed major bleeding complications; 67% of which occurred within the first month. No significant differences between DES and BMS were observed in the incidence of major (respectively 5.6% vs. 3.8%, p=1.0) and minor bleeding (respectively 1.4% vs. 3.8%, p=0.57) and mortality (respectively 5.6% vs. 1.9%, p=0.39). Four patients died in DES group: 3 of major bleeding complications and one of ischemic stroke. The only death in the BMS group was due to subarachnoid hemorrhage. A significant difference was observed in favor of DES in target vessel revascularization (14.1% vs. 28.3%, p=0.041).

Conclusions:
While on triple therapy, major bleeding complications occurred in 4.7% of patients, half of them were lethal and most (67%) occurred within the first month.
Abstract 2372: Validity of the MEDFICTS Dietary Assessment Questionnaire in a Diverse Population
Authors: Mochari Heidi , Gao Qian , Mosca Lori
Published: July 2021

Background:
The National Cholesterol Education Program (NCEP) recommends MEDFICTS, a rapid dietary fat screening instrument, for assessment of adherence to the Adult Treatment Panel (ATP) III Therapeutic Lifestyle Change (TLC) diet (Score < 40 points = < 7% of calories from saturated fat, <30% of calories from total fat, and <200mg dietary cholesterol/day). MEDFICTS has only been validated in small, select populations and its utility in diverse clinical settings is unknown. The purpose of this study was to evaluate the ability of MEDFICTS to identify individuals non-adherent to a TLC diet against a gold standard in an ethnically diverse population.

Methods:
MEDFICTS was administered concurrently with the Gladys Block Food Frequency Questionnaire to participants (n=470; 35% non-white; 66% female; mean age 48.1 ± 13.6y) in the NHLBI
F
amily
I
ntervention
T
rial for
Heart
Health (
F.I.T. Heart
) at the baseline screening visit. Correlation, agreement, sensitivity and specificity analyses were conducted overall and by sex, age, and race/ethnicity.

Results:
MEDFICTS score correlated significantly with % calories from saturated fat (r=.51, p<.0001), % calories from total fat (r=.30, p<.0001), and mg/day dietary cholesterol (r=.53, p=<.0001). Categorical agreement between MEDFICTS score <40 and Gladys Block on TLC diet adherence was poor overall (κ = 0.07) and for individual TLC components:

<7% calories from saturated fat (κ=.12),

<30% calories from total fat (κ=.16),

<200mg dietary cholesterol per day (κ=.34).

Sensitivity of MEDFICTS to correctly identify TLC diet adherence was 84% and did not differ significantly by sex, age, or race/ethnicity. Specificity of MEDFICTS to correctly identify non-adherence to TLC diet was low (57%) and was significantly worse for females than males (48% vs. 74%; p<.0001), but did not differ significantly in older vs. younger participants or among whites and non-whites.

Conclusion:
The NCEP ATP III MEDFICTS dietary assessment questionnaire performed poorly as a screening tool to correctly identify patients non-adherent to a TLC diet. Our data suggest a re-calibration of the instrument to improve specificity may increase its clinical utility.
Abstract 2375: Oseltamivir Treatment Reduces the Risk of Stroke Following Influenza Infection
Authors: Madjid Mohammad , Curkendall Suellen , Blumentals William A
Published: July 2021

Background:
Influenza infection is known to trigger the incidence of heart attack and ischemic stroke. Seasonal influenza epidemics are associated with an increased risk of cardiovascular diseases, including ischemic stroke. Influenza vaccine has been shown to reduce the risk of myocardial infarction and stroke. The antiviral drug oseltamivir has been shown to reduce the severity and duration of influenza symptoms and the risk of hospitalization in patients diagnosed with influenza. We conducted a retrospective cohort study to examine the impact of oseltamivir treatment on the risk of stroke and transient ischemic attack (TIA) following influenza in adults.

Methods:
Anonymous, patient-level medical and pharmaceutical claims data from May 2000 to September 2006 were obtained from a managed care database. We selected patients diagnosed with influenza who were prescribed oseltamivir within 1 day before or 2 days after influenza diagnosis (oseltamivir group) and compared them to patients who were not prescribed any antiviral treatment for influenza (control group). The incidence of stroke or TIA in the 6 months following influenza diagnosis in the two groups was compared using multivariate analyses adjusted for factors including age, gender, and history of risk factors for stroke, and differences expressed as hazard ratios (HR) with 95% confidence intervals (CI).

Results:
There were 151,930 eligible patients aged ≥18 years: 49,238 patients in the oseltamivir group, and 102,692 patients in the control group. Treatment with oseltamivir was associated with a significant 29% reduction in the risk of stroke or TIA at 6 months following an influenza diagnosis (HR=0.71; 95% CI 0.61– 0.81). Significant reductions in risk were also observed at 1 and 3 months. The effect of oseltamivir on the risk of stroke or TIA was more pronounced in patients aged ≥40 years: significant risk reductions were observed at months 1 (HR=0.50; 95% CI 0.37– 0.68), 3 (HR=0.62; 95% CI 0.51– 0.75), and 6 (HR=0.73; 95% CI 0.63– 0.84). In those aged <40, HR at 6 months was 0.56 (95% CI: 0.37– 0.86).

Conclusions:
Prescription of oseltamivir after influenza is associated with a reduced risk of stroke or TIA. Our results, once confirmed by randomized studies, offer a novel approach to prevent stroke and TIA.
Abstract 2381: Aneurysmal Subarachnoid Hemorrhage: Metabolic and Blood Flow Patterns
Authors: moftakhar parham , Glenn Thomas C , Boscardin John , Martin Neil A
Published: July 2021

Objective:
The purpose of this study is to classify and describe the clinically distinct metabolic and hemodynamic phases post-ASAH.

Methods:
224 patients who suffered an ASAH (mean age 55±14; 74% female, 26% male) were examined. Patients underwent daily transcranial Doppler (TCD) and cerebral blood flow (CBF) studies (using
133
Xe clearance). Due to the paucity of data on post-hemorrhage day (PHD) 0, the internal carotid artery end-diastolic (ICA
ED
) velocity, a surrogate for CBF, was used for the first 24 hours. The brain arteriovenous oxygen difference (AVDO
2
) was recorded for each patient and the cerebral metabolic rate of oxygen (CMRO
2
) was calculated. Clinical outcome was evaluated based on the Glasgow Outcome Scale (GOS) 6 months after rupture.

Results:
Following ASAH, 3 distinct hemodynamic phases arose for the entire study population. Phase I (hypoperfusion phase), occurs on the day of rupture (PHD 0) and is defined by a low ICA
ED
velocity (mean 17.8±1.1 cm/s), normal middle cerebral artery (MCA) velocity (mean V
MCA
58.0±23.4 cm/s), and normal Lindegaard Ratio ([LR], mean 1.66±0.50). Phase II (relative hyperemia), (PHD 1–3), is characterized by an increasing ICA
ED
(mean 35.4±1.0 cm/s, p<0.0001), a relative hyperemia (mean CBF
15
40.1±1.5 ml/100g/minute, CMRO
2
1.17±0.41 ml/100g/min), a rising V
MCA
(mean 71.5±5.8 cm/sec, p<0.0001), and a rising but normal LR (mean 2.21±0.19, p<0.0001). During phase III (vasospasm phase, PHD 4–21), both the ICA
ED
and CBF decrease (mean ICA
ED
19.9±0.9 cm/s, p<0.0001; mean CBF
15
36.8±0.7 ml/100g/minute, p=0.04), V
MCA
continues to rise (mean 107.6±2.9cm/sec, p<0.0001), and the LR is further increased (mean 3.25±0.08, p<0.0001). The CMRO
2
remains low (mean 1.17±0.40 ml/100g/min, p=1). Based on the GOS up to 90% of patients who experienced either a relative or absolute hyperemia had good outcomes.

Conclusions:
After an ASAH, 3 discrete metabolic and hemodynamic phases arise each with the potential for its own unique phase-specific management and therapy. Relative hyperemia, or “luxury perfusion,” during Phase II in the setting of non-elevated ICPs may provide some type of benefit for patients.